U.S. patent application number 15/027086 was filed with the patent office on 2016-09-08 for factor xia inhibitors.
This patent application is currently assigned to Merck Sharp & Dohme Corp.. The applicant listed for this patent is Scott D. EDMONDSON, Zhuyan GUO, Jiafang HE, Eric MERTZ, Santhosh NEELAMKAVIL, Ning SHAO, Yi ZANG. Invention is credited to Scott D. Edmondson, Zhuyan Guo, Jiafang He, Eric Mertz, Santhosh Neelamkavil, Ning Shao, Yi Zang.
Application Number | 20160257668 15/027086 |
Document ID | / |
Family ID | 52813534 |
Filed Date | 2016-09-08 |
United States Patent
Application |
20160257668 |
Kind Code |
A1 |
Shao; Ning ; et al. |
September 8, 2016 |
Factor XIa Inhibitors
Abstract
The present invention provides a compound of Formula (I)
##STR00001## and pharmaceutical compositions comprising one or more
said compounds, and methods for using said compounds for treating
or preventing thromboses, embolisms, hypercoagulability or fibrotic
changes. The compounds are selective Factor XIa inhibitors or dual
inhibitors of Factor XIa and plasma kallikrein.
Inventors: |
Shao; Ning; (Watchung,
NJ) ; Edmondson; Scott D.; (Clark, NJ) ;
Neelamkavil; Santhosh; (Edison, NJ) ; Guo;
Zhuyan; (Scotch Plains, NJ) ; Mertz; Eric;
(Somerset, NJ) ; Zang; Yi; (Princeton Junction,
NJ) ; He; Jiafang; (Dayton, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SHAO; Ning
EDMONDSON; Scott D.
NEELAMKAVIL; Santhosh
GUO; Zhuyan
MERTZ; Eric
ZANG; Yi
HE; Jiafang |
Watchung
Kenilworth
Kenilworth
Kenilworth
Kenilworth
Kenilworth
Kenilworth |
NJ
NJ
NJ
NJ
NJ
NJ
NJ |
US
US
US
US
US
US
US |
|
|
Assignee: |
Merck Sharp & Dohme
Corp.
Rahway
NJ
|
Family ID: |
52813534 |
Appl. No.: |
15/027086 |
Filed: |
October 6, 2014 |
PCT Filed: |
October 6, 2014 |
PCT NO: |
PCT/US14/59213 |
371 Date: |
April 4, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61887699 |
Oct 7, 2013 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/10 20130101;
C07C 269/06 20130101; C07D 401/14 20130101; C07D 413/14 20130101;
C07D 401/04 20130101 |
International
Class: |
C07D 401/14 20060101
C07D401/14; C07C 269/06 20060101 C07C269/06; C07D 401/10 20060101
C07D401/10 |
Claims
1. A compound of Formula I ##STR00086## or a pharmaceutically
acceptable salt thereof, wherein R.sup.2 is 1) aryl 2) R.sup.21, 3)
4-7-membered saturated carbocycle, 4) --OR.sup.21, or 5)
##STR00087## wherein R.sup.21 is 4-7-membered unsaturated or
saturated heterocycle containing one or two heteroatoms
independently selected from the N, O and S, wherein aryl is
unsubstituted or monosubstituted with CF.sub.3, and heterocycle is
unsubstituted or monosubstituted with NH.sub.2, SO.sub.2CH.sub.3 or
COCH.sub.3; R.sup.6 is 1) --CH.dbd.CH--R.sup.63, 2)
--CH.sub.2CH.sub.2--R.sup.63, 3) 4-7-membered monocyclic saturated
heterocycle having one or two heteroatoms independently selected
from N, O and S, 4) R.sup.62, 5) 7-9-membered bicyclic unsaturated
carbocycle, wherein R.sup.63 is aryl which is mono, di or
trisubstituted with a substituent independently selected from
halogen, CF.sub.3 and tetrazole, saturated heterocycle is
unsubstituted or substituted at the nitrogen atom with
--C(NH)NH.sub.2, and R.sup.62 is unsaturated or saturated
carbocycle unsubstituted or independently substituted with one or
two of --CH.sub.2NH.sub.2, NH.sub.2, C(CH.sub.3).sub.2NH.sub.2,
C.sub.1-6 alkyl, or C.sub.3-8 cycloalkyl, or 6) ##STR00088##
wherein R.sup.61 is --(CH.sub.2).sub.0-1NH.sub.2; R.sup.4 is 1)
--CH.sub.2OR.sup.41, wherein R.sup.41 is hydrogen or --Si(C.sub.1-6
alkyl)(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), 2) aryl, 3) 3-7-membered
monocyclic saturated carbocycle, 4) C.sub.1-6 alkyl, or 5)
--O--R.sup.42, wherein R.sup.42 is a 4-7-membered monocyclic
saturated heterocycle having one or two heteroatoms independently
selected from N, O and S, wherein aryl is unsubstituted or
substituted with one or two substituents independently selected
from CF.sub.3, halogen, NH.sub.2, OCF.sub.3, C(O)NH.sub.2,
C.sub.1-6 alkyl or ##STR00089## R.sup.5 is 1) --C(O)NHR.sup.51
wherein R.sup.51 is a) 3-7-membered monocyclic saturated or
unsaturated carbocycle, b) 8-membered bicyclic saturated
carbocycle, or c) 9-membered bicyclic unsaturated heterocycle
wherein carbocycle is unsubstituted or substituted with one or two
substituents independently selected from C(O)OC(C.sub.1-6
alkyl)(C.sub.1-6 alkyl)(C.sub.1-6 alkyl) or C(O)OH, and wherein
heterocycle containing one or two heteroatoms selected from N, O
and S, is unsubstituted or substituted with methyl, 2) ##STR00090##
wherein R.sup.52 is a) 3-7-membered monocyclic saturated or
unsaturated carbocycle, b) 6-membered unsaturated heterocycle
containing 1 nitrogen atom, or c) 9-membered bicyclic unsaturated
heterocycle containing 1 or 2 heteroatoms, selected from N and O
wherein carbocycle is unsubstituted or substituted with with one or
two substituents independently selected from CN, halogen,
OC.sub.1-6 alkyl, SO.sub.2C.sub.1-6 alkyl, CF.sub.3, C(O)OC.sub.1-6
alkyl, NH.sub.2, NHC(O)OC.sub.1-6 alkyl, NHC(O)C.sub.1-6 alkyl,
C(O)OC(CH.sub.3).sub.2, C(O)OH, PO.sub.3H.sub.2, or
PO.sub.3(C.sub.1-6 alkyl).sub.2, wherein heterocycle is
unsubstituted or substituted with methyl, and wherein bicyclic
heterocycle is unbsubstituted or substituted with a .dbd.O, and
R.sup.53 is hydrogen, halogen or C.sub.1-6 alkyl, and 3)
##STR00091## wherein R.sup.54 is hydrogen or halogen.
2. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is 1) phenyl 2) R.sup.21, 3) 5-6-membered
saturated carbocycle, 4) --OR.sup.21, or 5) ##STR00092## wherein
R.sup.21 is 5-6-membered saturated heterocycle containing one or
two N heteroatoms, wherein phenyl is unsubstituted or
monosubstituted with CF.sub.3, and saturated heterocycle is
unsubstituted or monosubstituted with NH.sub.2, SO.sub.2CH.sub.3 or
COCH.sub.3; R.sup.6 is 1) --CH.dbd.CH--R.sup.63, or 2) R.sup.62,
wherein R.sup.63 is phenyl which is mono, di or trisubstituted with
a substituent independently selected from halogen, CF.sub.3 and
tetrazole, and R.sup.62 is unsaturated carbocycle unsubstituted or
substituted with one or two substituents independently selected
from --CH.sub.2NH.sub.2, NH.sub.2, C(CH.sub.3).sub.2NH.sub.2,
C.sub.1-6 alkyl, or C.sub.3-8 cycloalkyl; R.sup.4 is 1) phenyl, 2)
cyclohexyl, 3) C.sub.1-6 alkyl, or 4) --OR.sup.42, wherein R.sup.42
is a 6-membered monocyclic saturated heterocycle having one or two
N atoms, wherein phenyl is unsubstituted or substituted with one or
two substituents independently selected from CF.sub.3, halogen,
NH.sub.2, OCF.sub.3, C(O)NH.sub.2, C.sub.1-6 alkyl or ##STR00093##
R.sup.5 is --C(O)NHR.sup.51 wherein R.sup.51 is a) 3-7 membered
monocyclic saturated or unsaturated carbocycle, b) 8 membered
bicyclic saturated carbocycle, or c) 9 membered bicyclic
unsaturated heterocycle, wherein carbocycle is unsubstituted or
unsubstituted with with one or two substituents independently
selected from C(O)OC(C.sub.1-6 alkyl)(C.sub.1-6 alkyl) or C(O)OH,
wherein heterocycle contains one or two heteroatoms selected from
N, O and S, and wherein heterocycle is unsubstituted or substituted
with methyl.
3. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is 1) phenyl, 2) cyclohexyl, 3) methyl or
ethyl, or 4) --O--R.sup.42, herein R.sup.42 is piperidinyl, wherein
phenyl is unsubstituted or substituted with one or two substituents
independently selected from CF.sub.3, halogen, NH.sub.2, OCF.sub.3,
C(O)NH.sub.2, C.sub.1-6 alkyl or ##STR00094##
4. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.6 is 1) --CH.dbd.CH--R.sup.63, or 2)
R.sup.62, wherein R.sup.63 is phenyl substituted with chloro and
tetrazole, and R.sup.62 is phenyl unsubstituted or substituted with
one or two substituents independently selected from
--CH.sub.2NH.sub.2, or cyclopropyl.
5. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.6 is ##STR00095##
6. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is 1) phenyl, or 2) cyclohexyl, 3) methyl
or ethyl, or 4) --O--R.sup.42.
7. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is ##STR00096##
8. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is --C(O)NHR.sup.51, wherein R.sup.51 is
a) phenyl, or b) 9 membered bicyclic unsaturated, unsubstituted
heterocycle containing one or two N atoms, wherein phenyl is
unsubstituted or unsubstituted with one or two of C(O)OH.
9. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is ##STR00097##
10. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is 1) phenyl 2) R.sup.21, 3) cyclohexyl,
4) --OR.sup.21, or 5) ##STR00098## wherein R.sup.21 is 6-membered
saturated heterocycle containing one or two N heteroatoms, wherein
phenyl is unsubstituted or monosubstituted with CF.sub.3, and
saturated heterocycle is unsubstituted or monosubstituted with
NH.sub.2, SO.sub.2CH.sub.3 or COCH.sub.3.
11. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is ##STR00099##
12. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, which is
(E)-4-(4-amino-1'-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylo-
yl)-5'-phenyl-[1,3'-bipiperidine]-6'-carboxamido)benzoic acid,
(E)-4-(1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(pi-
perazin-1-yl)piperidine-2-carboxamido)benzoic acid,
4-({[4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-
-5'-(1-methylethyl)-1,3'-bipiperidin-6'-yl]carbonyl}amino)benzoic
acid,
4-{[(4-amino-1'-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl-
}-5'-cyclopropyl-1,3'-bipiperidin-6'-yl)carbonyl]amino}benzoic
acid,
4-{[(4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-
-5'-methyl-1,3'-bipiperidin-6'-yl)carbonyl]amino}benzoic acid,
4-({[(3'S,5'S,6'S)-4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl-
]prop-2-enoyl}-5'-phenyl-1,3'-bipiperidin-6'-yl]carbonyl}amino)benzoic
acid,
4-({[(3'R,5'R,6'R)-4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)-
phenyl]prop-2-enoyl}-5'-phenyl-1,3'-bipiperidin-6'-yl]carbonyl}amino)benzo-
ic acid,
4-(4-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamido)-1'-(-
(E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5'-phenyl-[1,3'-bipip-
eridine]-6'-carboxamido)benzoic acid, 4-((2S,3
S,5S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5--
(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid,
4-((2R,3R,5R)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-p-
henyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid,
(E)-4-(1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(pi-
peridin-4-yloxy)piperidine-2-carboxamido)benzoic acid,
4-(1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-phenyl-3-(pi-
peridin-4-yloxy)piperidine-2-carboxamido)benzoic acid, methyl
(4-{2-[4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoy-
l}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-4-yl}phenyl)car-
bamate,
1'-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5'-(-
4-fluorophenyl)-6'-(4-pyridin-3-yl-1H-imidazol-2-yl)-1,3'-bipiperidin-4-am-
ine,
(3'S,5'S,6'S)-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-e-
noyl}-5'-(4-fluorophenyl)-6'-(4-pyridin-3-yl-1H-imidazol-2-yl)-1,3'-bipipe-
ridin-4-amine,
4-{2-[4-amino-1'-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]pro-
p-2-enoyl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-5-yl}be-
nzonitrile,
4-{2-[4-amino-1'-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]pro-
p-2-enoyl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-5-yl}be-
nzonitrile,
4-{2-[4-amino-1'-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoy-
l}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-5-yl}benzonitri-
le, methyl
(4-{2-[4-amino-1'-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl-
)phenyl]prop-2-enoyl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imida-
zol-5-yl}phenyl)carbamate, methyl
(4-{2-[4-amino-1'-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]pr-
op-2-enoyl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-5-yl}p-
henyl)carbamate, methyl
[4-(2-{4-amino-1'-[(2E)-3-(3-chloro-2,6-difluorophenyl)prop-2-enoyl]-5'-(-
4-fluorophenyl)-1,3'-bipiperidin-6'-yl}-1H-imidazol-4-yl)phenyl]carbamate,
methyl
(4-{2-[(3'S,5'S,6'S)-4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1--
yl)phenyl]prop-2-enoyl}-5'-cyclopropyl-1,3'-bipiperidin-6'-yl]-1H-imidazol-
-4-yl}phenyl)carbamate, 4-((3R,5 S,6
S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-phenyl-[3,4'-
-bipiperidine]-6-carboxamido)benzoic acid trifluoroacetic acid
salt, 4-((3R,5R,6
S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-methyl-[3,4'-
-bipiperidine]-6-carboxamido)benzoic acid,
4-((3R,5R,6S)-1-(4-(aminomethyl)-3-cyclopropylbenzoyl)-5-methy-1-[3,4'-bi-
piperidine]-6-carboxamido)benzoic acid, methyl
(4-{2-[(3R,5S,6S)-1-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-en-
oyl}-5-cyclopropyl-3,4'-bipiperidin-6-yl]-1H-imidazol-4-yl}phenyl)carbamat-
e, methyl
(4-{2-[1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-eno-
yl}-5-(4-fluorophenyl)-3,4'-bipiperidin-6-yl]-1H-imidazol-4-yl}phenyl)carb-
amate, methyl
(4-{2-[(3R,5S,6S)-1-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-en-
oyl}-5-cyclopropyl-1'-(methylsulfonyl)-3,4'-bipiperidin-6-yl]-1H-imidazol--
4-yl}phenyl)carbamate,
(2S,3S,5S)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-3-
-(4-fluorophenyl)-N-1H-indazol-5-yl-5-morpholin-4-ylpiperidine-2-carboxami-
de,
(2R,3R,5R)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl-
}-3-(4-fluorophenyl)-N-1H-indazol-5-yl-5-piperazin-1-ylpiperidine-2-carbox-
amide,
(2S,3S,5S)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-en-
oyl}-3-(4-fluorophenyl)-N-1H-indazol-5-yl-5-piperazin-1-ylpiperidine-2-car-
boxamide,
(2S,3S,5S)-5-(4-acetylpiperazin-1-yl)-1-{(2E)-3-[5-chloro-2-(1H--
tetrazol-1-yl)phenyl]prop-2-enoyl}-3-(4-fluorophenyl)-N-1H-indazol-5-ylpip-
eridine-2-carboxamide.
13. A composition for inhibiting thrombus formation in blood
comprising a compound of claim 1, or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier.
14. A method for inhibiting thrombin in blood comprising adding to
the blood a composition of claim 13.
15. A method for inhibiting formation of blood platelet aggregates
in blood comprising adding to the blood a composition of claim
13.
16. A method for inhibiting thrombus formation in blood comprising
adding to the blood a composition of claim 13.
17. (canceled)
18. A method for treating or preventing venous thromboembolism and
pulmonary embolism in a mammal comprising administering to the
mammal a composition of claim 13.
19. A method for treating or preventing deep vein thrombosis in a
mammal comprising administering to the mammal a composition of
claim 13.
20. A method for treating or preventing thromboembolic stroke in
humans and other mammals comprising administering to the mammal a
composition of claim 13.
Description
BACKGROUND OF THE INVENTION
[0001] Factor XIa is a plasma serine protease involved in the
regulation of blood coagulation. While blood coagulation is a
necessary and important part of the regulation of an organism's
homeostasis, abnormal blood coagulation can also have deleterious
effects. For instance, thrombosis is the formation or presence of a
blood clot inside a blood vessel or cavity of the heart. Such a
blood clot can lodge in a blood vessel blocking circulation and
inducing a heart attack or stroke. Thromboembolic disorders are the
largest cause of mortality and disability in the industrialized
world.
[0002] Blood clotting is a process of control of the blood stream
essential for the survival of mammals. The process of clotting, and
the subsequent dissolution of the clot after wound healing has
taken place, commence after vascular damage, and can be divided
into four phases. The first phase, vasoconstriction or
vasocontraction, can cause a decrease in blood loss in the damaged
area. In the next phase, platelet activation by thrombin, platelets
attach to the site of the vessel wall damage and form a platelet
aggregate. In the third phase, formation of clotting complexes
leads to massive formation of thrombin, which converts soluble
fibrinogen to fibrin by cleavage of two small peptides. In the
fourth phase, after wound healing, the thrombus is dissolved by the
action of the key enzyme of the endogenous fibrinolysis system,
plasmin.
[0003] Two alternative pathways can lead to the formation of a
fibrin clot, the intrinsic and the extrinsic pathway. These
pathways are initiated by different mechanisms, but in the later
phase they converge to give a common final path of the clotting
cascade. In this final path of clotting, clotting Factor X is
activated. The activated Factor X is responsible for the formation
of thrombin from the inactive precursor prothrombin circulating in
the blood. The formation of a thrombus on the bottom of a vessel
wall abnormality without a wound is the result of the intrinsic
pathway. Fibrin clot formation as a response to tissue damage or an
injury is the result of the extrinsic pathway. Both pathways
comprise a relatively large number of proteins, which are known as
clotting factors. The intrinsic pathway requires the clotting
Factors V, VIII, IX, X, XI and XII and also prekallikrein, high
molecular weight kininogen, calcium ions and phospholipids from
platelets. The activation of Factor XIa is a central point of
intersection between the two pathways of activation of clotting.
Factor XIa has an important role in blood clotting.
[0004] Coagulation is initiated when blood is exposed to artificial
surfaces (e.g., during hemodialysis, "on-pump" cardiovascular
surgery, vessel grafts, bacterial sepsis), on cell surfaces,
cellular receptors, cell debris, DNA, RNA, and extracellular
matrices. This process is also termed contact activation. Surface
absorption of Factor XII leads to a conformational change in the
Factor XII molecule, thereby facilitating activation to proteolytic
active Factor XII molecules (Factor XIIa and Factor XIIf) Factor
XIIa (or XIIf) has a number of target proteins, including plasma
prekallikrein and Factor XI. Active plasma kallikrein further
activates Factor XII, leading to an amplification of contact
activation. Alternatively, the serine protease
prolylcarboxylpeptidase can activate plasma kallikrein complexed
with high molecular weight kininogen in a multiprotein complex
formed on the surface of cells and matrices (Shariat-Madar et al.,
Blood, 108:192-199 (2006)). Contact activation is a surface
mediated process responsible in part for the regulation of
thrombosis and inflammation, and is mediated, at least in part, by
fibrinolytic-, complement-, kininogen/kinin-, and other humoral and
cellular pathways (for review, Coleman, R., "Contact Activation
Pathway", Hemostasis and Thrombosis, pp. 103-122, Lippincott
Williams & Wilkins (2001); Schmaier, A. H., "Contact
Activation", Thrombosis and Hemorrhage, pp. 105-128 (1998)). The
biological relevance of the contact activation system for
thromboembolic 5 diseases is supported by the phenotype of Factor
XII deficient mice. More specifically, Factor XII deficient mice
were protected from thrombotic vascular occlusion in several
thrombosis models as well as stroke models and the phenotype of the
XII deficient mice was identical to XI deficient mice (Renne et
al., J Exp. Med., 202:271-281 (2005); Kleinschmitz et al., J Exp.
Med., 203:513-518 (2006)). The fact that Factor XI is downstream
from Factor XIIa, combined with the identical phenotype of the XII
and XI deficient mice suggest that the contact activation system
could play a major role in Factor XI activation in vivo. Plasma
kallikrein is a zymogen of a trypsin-like serine protease and is
present in plasma. The gene structure is similar to that of Factor
XI. Overall, the amino acid sequence of plasma kallikrein has 58%
homology to Factor XI. Proteolytic activation by Factor XIIa at an
internal I 389-R390 bond yields a heavy chain (371 amino acids) and
a light chain (248 amino acids). The active site of plasma
kallikrein is contained in the light chain. The light chain of
plasma kallikrein reacts with protease 15 inhibitors, including
alpha 2 macroglobulin and Cl-inhibitor. Interestingly, heparin
significantly accelerates the inhibition of plasma kallikrein by
antithrombin III in the presence of high molecular weight kininogen
(HMWK). In blood, the majority of plasma kallikrein circulates in
complex with HMWK. Plasma kallikrein cleaves HMWK to liberate
bradykinin. Bradykinin release results in increase of vascular
permeability and vasodilation (for review, Coleman, R., "Contact
Activation Pathway", Hemostasis and Thrombosis, pp. 103-122,
Lippincott Williams & Wilkins (2001); Schmaier A. H., "Contact
Activation", Thrombosis and Hemorrhage, pp. 105-128 (1998)).
[0005] Factor XIa inhibitor compounds are described in
WO2013022814, WO 2013022814, WO 2013022818, WO 2013055984,
WO2013056034, WO2013056060, WO2013118805. WO2013093484.
WO2002042273, WO2002037937, WO2002060894, WO2003015715,
WO2004002405, US20040180855, WO2004080971, WO2004094372,
US20050228000, US20050282805, WO2005123680, US20090036438,
US20120088758, US20060074103, WO2006062972, WO2006076246,
US20060154915, US20090062287, US20060183771, WO2007070818,
WO2007070816, WO2007070826, WO2008076805, WO2008157162,
WO2009114677, WO2011100402, and WO2011100401.
SUMMARY OF THE INVENTION
[0006] The present invention relates to compounds of Formula I:
##STR00002##
or pharmaceutically acceptable salts thereof. The compounds of
Formula I are selective Factor XIa inhibitors or dual inhibitors of
Factor XIa and plasma kallikrein, and as such may be useful in the
treatment, inhibition or amelioration of one or more disease states
that could benefit from inhibition of Factor XIa or plasma
kallikrein, including thromboses, embolisms, hypercoagulability or
fibrotic changes. The compounds of this invention could further be
used in combination with other therapeutically effective agents,
including but not limited to, other drugs useful for the treatment
of thromboses, embolisms, hypercoagulability or fibrotic changes.
The invention furthermore relates to processes for preparing
compounds of Formula I, and pharmaceutical compositions which
comprise compounds of Formula I and pharmaceutically acceptable
salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The invention includes compounds of formula I
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein
R.sup.2 is
[0008] 1) aryl [0009] 2) R.sup.21, [0010] 3) 4-7-membered saturated
carbocycle, [0011] 4) --OR.sup.21, or [0012] 5)
[0012] ##STR00004## [0013] wherein R.sup.21 is 4-7-membered
unsaturated or saturated heterocycle containing one or two
heteroatoms independently selected from N, O and S, [0014] wherein
aryl is unsubstituted or monosubstituted with CF.sub.3, and
heterocycle is unsubstituted or monosubstituted with NH.sub.2,
SO.sub.2CH.sub.3 or COCH.sub.3;
R.sup.6 is
[0014] [0015] 1) --CH.dbd.CH--R.sup.63, [0016] 2)
--CH.sub.2CH.sub.2--R.sup.63, [0017] 3) 4-7 membered monocyclic
saturated heterocycle having one or two heteroatoms independently
selected from N, O and S, [0018] 4) R.sup.62, [0019] 5)
7-9-membered bicyclic unsaturated carbocycle, [0020] wherein
R.sup.63 is aryl which is mono, di or trisubstituted with a
substituent independently selected from halogen, CF.sub.3 and
tetrazole, saturated heterocycle is unsubstituted or substituted at
the nitrogen atom with --C(NH)NH.sub.2, and R.sup.62 is unsaturated
or saturated carbocycle unsubstituted or independently substituted
with one or two of --CH.sub.2NH.sub.2, NH.sub.2,
C(CH.sub.3).sub.2NH.sub.2, C.sub.1-6 alkyl, or C.sub.3-8
cycloalkyl, or [0021] 6)
[0021] ##STR00005## wherein R.sup.61 is
--(CH.sub.2).sub.0-1NH.sub.2;
R.sup.4 is
[0022] 1) --CH.sub.2OR.sup.41, wherein R.sup.41 is hydrogen or
--Si(C.sub.1-6 alkyl)(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), [0023] 2)
aryl, [0024] 3) 3-7-membered monocyclic saturated carbocycle,
[0025] 4) C.sub.1-6 alkyl, or [0026] 5) --O--R.sup.42, wherein
R.sup.42 is a 4-7-membered monocyclic saturated heterocycle having
one or two heteroatoms independently selected from N, O and S,
[0027] wherein aryl is unsubstituted or substituted with one or two
substituents independently selected from CF.sub.3, halogen,
NH.sub.2, OCF.sub.3, C(O)NH.sub.2, C.sub.1-6 alkyl or
##STR00006##
[0027] R.sup.5 is
[0028] 1) --C(O)NHR.sup.51 wherein [0029] R.sup.51 is [0030] a)
3-7-membered monocyclic saturated or unsaturated carbocycle, [0031]
b) 8-membered bicyclic saturated carbocycle, or [0032] c)
9-membered bicyclic unsaturated heterocycle [0033] wherein
carbocycle is unsubstituted or substituted with one or two
substituents independently selected from C(O)OC(C.sub.1-6
alkyl)(C.sub.1-6 alkyl)(C.sub.1-6 alkyl) or C(O)OH, and wherein
heterocycle containing one or two heteroatoms selected from N, O
and S, is unsubstituted or substituted with methyl, [0034] 2)
[0034] ##STR00007## wherein [0035] R.sup.52 is [0036] a)
3-7-membered monocyclic saturated or unsaturated carbocycle, [0037]
b) 6-membered unsaturated heterocycle containing 1 nitrogen atom,
or [0038] c) 9-membered bicyclic unsaturated heterocycle containing
1 or 2 heteroatoms, selected from N and O [0039] wherein carbocycle
is unsubstituted or substituted with one or two substituents
independently selected from CN, halogen, OC.sub.1-6 alkyl,
SO.sub.2C.sub.1-6 alkyl, CF.sub.3, C(O)OC.sub.1-6 alkyl, NH.sub.2,
NHC(O)OC.sub.1-6 alkyl, NHC(O)C.sub.1-6 alkyl,
C(O)OC(CH.sub.3).sub.2, C(O)OH, PO.sub.3H.sub.2, or
PO.sub.3(C.sub.1-6 alkyl).sub.2, wherein heterocycle is
unsubstituted or substituted with methyl, and wherein bicyclic
heterocycle is unbsubstituted or substituted with a .dbd.O, and
[0040] R.sup.53 is hydrogen, halogen or C.sub.1-6 alkyl, and [0041]
3)
[0041] ##STR00008## wherein [0042] R.sup.54 is hydrogen or
halogen.
[0043] In one embodiment of the invention,
R.sup.2 is
[0044] 1) phenyl [0045] 2) R.sup.21, [0046] 3) 5-6-membered
saturated carbocycle, [0047] 4) --OR.sup.21, or [0048] 5)
[0048] ##STR00009## [0049] wherein R.sup.21 is 5-6-membered
saturated heterocycle containing one or two N heteroatoms, [0050]
wherein phenyl is unsubstituted or monosubstituted with CF.sub.3,
and saturated heterocycle is unsubstituted or monosubstituted with
NH.sub.2, SO.sub.2CH.sub.3 or COCH.sub.3;
R.sup.6 is
[0050] [0051] 1) --CH.dbd.CH--R.sup.63, or [0052] 2) R.sup.62,
[0053] wherein R.sup.63 is phenyl wherein R.sup.63 is aryl which is
mono, di or trisubstituted with a substituent independently
selected from halogen, CF.sub.3 and tetrazole, and R.sup.62 is
unsaturated carbocycle unsubstituted or substituted with one or two
substituents independently selected from --CH.sub.2NH.sub.2,
NH.sub.2, C(CH.sub.3).sub.2NH.sub.2, C.sub.1-6 alkyl, or C.sub.3-8
cycloalkyl;
R.sup.4 is
[0053] [0054] 1) phenyl, or [0055] 2) cyclohexyl, [0056] 3)
C.sub.1-6 alkyl, or [0057] 4) --OR.sup.42, wherein R.sup.42 is a
6-membered monocyclic saturated heterocycle having one or two N
atoms, [0058] wherein phenyl is unsubstituted or substituted with
one or two substituents independently selected from CF.sub.3,
halogen, NH.sub.2, OCF.sub.3, C(O)NH.sub.2, C.sub.1-6 alkyl or
##STR00010##
[0058] R.sup.5 is
[0059] --C(O)NHR.sup.51 wherein [0060] R.sup.51 is [0061] a)
3-7-membered monocyclic saturated or unsaturated carbocycle, [0062]
b) 8-membered bicyclic saturated carbocycle, or [0063] c)
9-membered bicyclic unsaturated heterocycle, [0064] wherein
carbocycle is unsubstituted or substituted with one or two
substituents independently selected from C(O)OC(C.sub.1-6
alkyl)(C.sub.1-6 alkyl) or C(O)OH, wherein heterocycle contains one
or two heteroatoms selected from N, O and S, and wherein
heterocycle is unsubstituted or substituted with methyl.
[0065] In another embodiment of the invention, R.sup.4 is
1) phenyl, 2) cyclohexyl, 3) methyl or ethyl, or 4) --O--R.sup.42,
wherein R.sup.42 is piperidinyl, wherein phenyl is unsubstituted or
substituted with one or two substituents independently selected
from CF.sub.3, halogen, NH.sub.2, OCF.sub.3, C(O)NH.sub.2,
C.sub.1-6 alkyl or
##STR00011##
[0066] In another embodiment of the invention, R.sup.6 is
1) --CH.dbd.CH--R.sup.63, or
2) R.sup.62,
[0067] wherein R.sup.63 is phenyl substituted with chloro and
tetrazole, and R.sup.62 is phenyl unsubstituted or substituted with
one or two substituents independently selected from
--CH.sub.2NH.sub.2, or cyclopropyl.
[0068] In another embodiment of the invention, R.sup.6 is
##STR00012##
[0069] In another embodiment of the invention, R.sup.4 is
1) phenyl, 2) cyclohexyl, 3) methyl or ethyl, or
4) --O--R.sup.42.
[0070] In another embodiment of the invention, R.sup.4 is
##STR00013##
[0071] In another embodiment of the invention, R.sup.5 is
--C(O)NHR.sup.51, wherein R.sup.51 is [0072] a) phenyl, or [0073]
b) 9-membered bicyclic unsaturated, unsubstituted heterocycle
containing one or two N atoms, [0074] wherein phenyl is
unsubstituted or substituted with one or two of C(O)OH.
[0075] In another embodiment of the invention, R.sup.5 is
##STR00014##
[0076] In another embodiment of the invention,
R.sup.2 is
[0077] 1) phenyl [0078] 2) R.sup.21, [0079] 3) cyclohexyl, [0080]
4) --OR.sup.21, or [0081] 5)
[0081] ##STR00015## [0082] wherein R.sup.21 is 6-membered saturated
heterocycle containing one or two N heteroatoms, [0083] wherein
phenyl is unsubstituted or monosubstituted with CF.sub.3, and
saturated heterocycle is unsubstituted or monosubstituted with
NH.sub.2;
[0084] In another embodiment of the invention, R.sup.2 is
##STR00016##
[0085] In another embodiment of the invention, the compound is
[0086]
(E)-4-(4-amino-1'-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5'-ph-
enyl-[1,3'-bipiperidine]-6'-carboxamido)benzoic acid, [0087]
(E)-4-(1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(pi-
perazin-1-yl)piperidine-2-carboxamido)benzoic acid, [0088]
4-({[(4-amino-1'-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoy-
l}-5'-(1-methylethyl)-1,3'-bipiperidin-6'-yl]carbonyl}amino)benzoic
acid, [0089]
4-{[(4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-
-enoyl}-5'-cyclopropyl-1,3'-bipiperidin-6'-yl)carbonyl]amino}benzoic
acid, [0090]
4-{[(4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-
-enoyl}-5'-methyl-1,3'-bipiperidin-6'-yl)carbonyl]amino}benzoic
acid, [0091]
4-({[(3'S,5'S,6'S)-4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl-
)phenyl]prop-2-enoyl}-5'-phenyl-1,3'-bipiperidin-6'-yl]carbonyl}amino)benz-
oic acid, [0092]
4-({[(3'R,5'R,6'R)-4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl-
]prop-2-enoyl}-5'-phenyl-1,3'-bipiperidin-6'-yl]carbonyl}amino)benzoic
acid, [0093]
4-(4-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamido)-1'-((E)-3-(5-
-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5'-phenyl-[1,3'-bipiperidine]-
-6'-carboxamido)benzoic acid, [0094] 4-((2S,3 S,5
S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(pi-
peridin-4-yloxy)piperidine-2-carboxamido)benzoic acid, [0095]
4-((2R,3R,5R)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-p-
henyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid,
[0096]
(E)-4-(1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(pi-
peridin-4-yloxy)piperidine-2-carboxamido)benzoic acid, [0097]
4-(1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-phenyl-3-(pi-
peridin-4-yloxy)piperidine-2-carboxamido)benzoic acid, [0098]
methyl
(4-{2-[4-amino-1'-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-eno-
yl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-4-yl}phenyl)ca-
rbamate, [0099]
1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5'-(4-fluoro-
phenyl)-6'-(4-pyridin-3-yl-1H-imidazol-2-yl)-1,3'-bipiperidin-4-amine,
[0100]
(3'S,5'S,6'S)-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop--
2-enoyl}-5'-(4-fluorophenyl)-6'-(4-pyridin-3-yl-1H-imidazol-2-yl)-1,3'-bip-
iperidin-4-amine, [0101]
4-{2-[4-amino-1'-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]pro-
p-2-enoyl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-5-yl}be-
nzonitrile, [0102]
4-{2-[4-amino-1'-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]pro-
p-2-enoyl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-5-yl}be-
nzonitrile, [0103]
4-{2-[4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl-
}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-5-yl}benzonitril-
e, [0104] methyl
(4-{2-[4-amino-1'-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]pr-
op-2-enoyl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-5-yl}p-
henyl)carbamate, [0105] methyl
(4-{2-[4-amino-1'-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]pr-
op-2-enoyl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-5-yl}p-
henyl)carbamate, [0106] methyl
[4-(2-{4-amino-1'-[(2E)-3-(3-chloro-2,6-difluorophenyl)prop-2-enoyl]-5'-(-
4-fluorophenyl)-1,3'-bipiperidin-6'-yl}-1H-imidazol-4-yl)phenyl]carbamate,
[0107] methyl
(4-{2-[(3'S,5'S,6'S)-4-amino-1'-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phen-
yl]prop-2-enoyl}-5'-cyclopropyl-1,3'-bipiperidin-6'-yl]-1H-imidazol-4-yl}p-
henyl)carbamate, [0108]
4-((3R,5S,6S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-p-
henyl-[3,4'-bipiperidine]-6-carboxamido)benzoic acid
trifluoroacetic acid salt, [0109]
4-((3R,5R,6S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-m-
ethyl-[3,4'-bipiperidine]-6-carboxamido)benzoic acid, [0110]
4-((3R,5R,6S)-1-(4-(aminomethyl)-3-cyclopropylbenzoyl)-5-methy-1-[3,4'-bi-
piperidine]-6-carboxamido) benzoic acid, [0111] methyl
(4-{2-[(3R,5S,6S)-1-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-en-
oyl}-5-cyclopropyl-3,4'-bipiperidin-6-yl]-1H-imidazol-4-yl}phenyl)carbamat-
e, [0112] methyl
(4-{2-[1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5-(4--
fluorophenyl)-3,4'-bipiperidin-6-yl]-1H-imidazol-4-yl}phenyl)carbamate,
[0113] methyl
(4-{2-[(3R,5S,6S)-1-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-en-
oyl}-5-cyclopropyl-1'-(methylsulfonyl)-3,4'-bipiperidin-6-yl]-1H-imidazol--
4-yl}phenyl)carbamate, [0114]
(2S,3S,5S)-1-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-3--
(4-fluorophenyl)-N-1H-indazol-5-yl-5-morpholin-4-ylpiperidine-2-carboxamid-
e, [0115]
(2R,3R,5R)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-
-enoyl}-3-(4-fluorophenyl)-N-1H-indazol-5-yl-5-piperazin-1-ylpiperidine-2--
carboxamide, [0116]
(2S,3S,5S)-1-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-3--
(4-fluorophenyl)-N-1H-indazol-5-yl-5-piperazin-1-ylpiperidine-2-carboxamid-
e, [0117]
(2S,3S,5S)-5-(4-acetylpiperazin-1-yl)-1-{(2E)-3-[5-chloro-2-(1H--
tetrazol-1-yl)phenyl]prop-2-enoyl}-3-(4-fluorophenyl)-N-1H-indazol-5-ylpip-
eridine-2-carboxamide, or a pharmaceutically acceptable salt
thereof.
[0118] Reference to the preferred classes and subclasses set forth
above is meant to include all combinations of particular and
preferred groups unless stated otherwise.
[0119] Specific embodiments of the present invention include, but
are not limited to the compounds identified herein as Examples 1 to
32, or pharmaceutically acceptable salts thereof.
[0120] Also included within the scope of the present invention is a
pharmaceutical composition which is comprised of a compound of
Formula I as described above and a pharmaceutically acceptable
carrier. The invention is also contemplated to encompass a
pharmaceutical composition which is comprised of a pharmaceutically
acceptable carrier and any of the compounds specifically disclosed
in the present application. These and other aspects of the
invention will be apparent from the teachings contained herein.
[0121] The invention also includes compositions for inhibiting loss
of blood platelets, inhibiting formation of blood platelet
aggregates, inhibiting formation of fibrin, inhibiting thrombus
formation, inhibiting embolus formation, and treating inflammatory
disorders in a mammal, comprising a compound of the invention in a
pharmaceutically acceptable carrier. These compositions may
optionally include anticoagulants, antiplatelet agents, and
thrombolytic agents. The compositions can be added to blood, blood
products, or mammalian organs in order to effect the desired
inhibitions.
[0122] The invention also includes compositions for preventing or
treating unstable angina, refractory angina, myocardial infarction,
transient ischemic attacks, atrial fibrillation, thrombotic stroke,
embolic stroke, deep vein thrombosis, disseminated intravascular
coagulation, ocular build up of fibrin, and reocclusion or
restenosis of recanalized vessels, in a mammal, comprising a
compound of the invention in a pharmaceutically acceptable carrier.
These compositions may optionally include anticoagulants,
antiplatelet agents, and thrombolytic agents.
[0123] The invention also includes a method for reducing the
thrombogenicity of a surface in a mammal by attaching to the
surface, either covalently or noncovalently, a compound of the
invention.
[0124] Compounds of the invention are Factor XIa inhibitors and may
have therapeutic value in, for example, preventing coronary artery
disease. The compounds are selective Factor XIa inhibitors or dual
inhibitors of Factor XIa and plasma kallikrein.
[0125] It will be understood that, as used herein, references to
the compounds of structural Formula I are meant to also include the
pharmaceutically acceptable salts, and also salts that are not
pharmaceutically acceptable when they are used as precursors to the
free compounds or their pharmaceutically acceptable salts or in
other synthetic manipulations.
[0126] The compounds of the present invention may be administered
in the form of a pharmaceutically acceptable salt. The term
"pharmaceutically acceptable salt" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids including
inorganic or organic bases and inorganic or organic acids. Salts of
basic compounds encompassed within the term "pharmaceutically
acceptable salt" refer to non-toxic salts of the compounds of this
invention which are generally prepared by reacting the free base
with a suitable organic or inorganic acid. Representative salts of
basic compounds of the present invention include, but are not
limited to, the following: acetate, ascorbate, adipate, alginate,
aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, butyrate, camphorate,
camphorsulfonate, camsylate, carbonate, chloride, clavulanate,
citrate, cyclopentane propionate, diethylacetic, digluconate,
dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate,
esylate, ethanesulfonate, formic, fumarate, gluceptate,
glucoheptanoate, gluconate, glutamate, glycerophosphate,
glycollylarsanilate, hemi sulfate, heptanoate, hexanoate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic,
isothionate, lactate, lactobionate, laurate, malate, maleate,
mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate,
nicotinate, nitrate, N-methylglucamine ammonium salt, oleate,
oxalate, pamoate (embonate), palmitate, pantothenate, pectinate,
persulfate, phosphate/diphosphate, pimelic, phenylpropionic,
polygalacturonate, propionate, salicylate, stearate, sulfate,
subacetate, succinate, tannate, tartrate, teoclate, thiocyanate,
tosylate, triethiodide, trifluoroacetate, undeconate, valerate and
the like. Furthermore, where the compounds of the invention carry
an acidic moiety, suitable pharmaceutically acceptable salts
thereof include, but are not limited to, salts derived from
inorganic bases including aluminum, ammonium, calcium, copper,
ferric, ferrous, lithium, magnesium, manganic, mangamous,
potassium, sodium, zinc, and the like. Also included are the
ammonium, calcium, magnesium, potassium, and sodium salts. Salts
derived from pharmaceutically acceptable organic non-toxic bases
include salts of primary, secondary, and tertiary amines, cyclic
amines, dicyclohexyl amines and basic ion-exchange resins, such as
arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethylamine, trimethylamine, tripropylamine, tromethamine, and
the like. Also, included are the basic nitrogen-containing groups
may be quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl, and butyl chloride, bromides and iodides;
dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides and others.
[0127] These salts can be obtained by known methods, for example,
by mixing a compound of the present invention with an equivalent
amount and a solution containing a desired acid, base, or the like,
and then collecting the desired salt by filtering the salt or
distilling off the solvent. The compounds of the present invention
and salts thereof may form solvates with a solvent such as water,
ethanol, or glycerol. The compounds of the present invention may
form an acid addition salt and a salt with a base at the same time
according to the type of substituent of the side chain.
[0128] The present invention encompasses all stereoisomeric forms
of the compounds of Formula I. Centers of asymmetry that are
present in the compounds of Formula I can all independently of one
another have (R) configuration or (S) configuration. When bonds to
the chiral carbon are depicted as straight lines in the structural
Formulas of the invention, it is understood that both the (R) and
(S) configurations of the chiral carbon, and hence both enantiomers
and mixtures thereof, are embraced within the Formula. When a
particular configuration is depicted, that entantiomer (either (R)
or (S), at that center) is intended. Similarly, when a compound
name is recited without a chiral designation for a chiral carbon,
it is understood that both the (R) and (S) configurations of the
chiral carbon, and hence individual enantiomers and mixtures
thereof, are embraced by the name. The production of specific
stereoisomers or mixtures thereof may be identified in the Examples
where such stereoisomers or mixtures were obtained, but this in no
way limits the inclusion of all stereoisomers and mixtures thereof
from being within the scope of this invention.
[0129] The invention includes all possible enantiomers and
diastereomers and mixtures of two or more stereoisomers, for
example mixtures of enantiomers and/or diastereomers, in all
ratios. Thus, enantiomers are a subject of the invention in
enantiomerically pure form, both as levorotatory and as
dextrorotatory antipodes, in the form of racemates and in the form
of mixtures of the two enantiomers in all ratios. In the case of a
cis/trans isomerism the invention includes both the cis form and
the trans form as well as mixtures of these forms in all ratios.
The preparation of individual stereoisomers can be carried out, if
desired, by separation of a mixture by customary methods, for
example by chromatography or crystallization, by the use of
stereochemically uniform starting materials for the synthesis or by
stereoselective synthesis. Optionally a derivatization can be
carried out before a separation of stereoisomers. The separation of
a mixture of stereoisomers can be carried out at an intermediate
step during the synthesis of a compound of Formula I or it can be
done on a final racemic product. Absolute stereochemistry may be
determined by X-ray crystallography of crystalline products or
crystalline intermediates which are derivatized, if necessary, with
a reagent containing a stereogenic center of known configuration.
Where compounds of this invention are capable of tautomerization,
all individual tautomers as well as mixtures thereof are included
in the scope of this invention. The present invention includes all
such isomers, as well as salts, solvates (including hydrates) and
solvated salts of such racemates, enantiomers, diastereomers and
tautomers and mixtures thereof.
[0130] In the compounds of the invention, the atoms may exhibit
their natural isotopic abundances, or one or more of the atoms may
be artificially enriched in a particular isotope having the same
atomic number, but an atomic mass or mass number different from the
atomic mass or mass number predominantly found in nature. The
present invention is meant to include all suitable isotopic
variations of the specifically and generically described compounds.
For example, different isotopic forms of hydrogen (H) include
protium (.sup.1H) and deuterium (.sup.2H). Protium is the
predominant hydrogen isotope found in nature. Enriching for
deuterium may afford certain therapeutic advantages, such as
increasing in vivo half-life or reducing dosage requirements, or
may provide a compound useful as a standard for characterization of
biological samples. Isotopically-enriched compounds can be prepared
without undue experimentation by conventional techniques well known
to those skilled in the art or by processes analogous to those
described in the general process schemes and examples herein using
appropriate isotopically-enriched reagents and/or
intermediates.
[0131] When any variable (e.g. R.sup.4, etc.) occurs more than one
time in any constituent, its definition on each occurrence is
independent at every other occurrence. Also, combinations of
substituents and variables are permissible only if such
combinations result in stable compounds. Lines drawn into the ring
systems from substituents represent that the indicated bond may be
attached to any of the substitutable ring atoms. If the ring system
is bicyclic, it is intended that the bond be attached to any of the
suitable atoms on either ring of the bicyclic moiety.
[0132] It is understood that one or more silicon (Si) atoms can be
incorporated into the compounds of the instant invention in place
of one or more carbon atoms by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
readily synthesized by techniques known in the art from readily
available starting materials. Carbon and silicon differ in their
covalent radius leading to differences in bond distance and the
steric arrangement when comparing analogous C-element and
Si-element bonds. These differences lead to subtle changes in the
size and shape of silicon-containing compounds when compared to
carbon. One of ordinary skill in the art would understand that size
and shape differences can lead to subtle or dramatic changes in
potency, solubility, lack of off-target activity, packaging
properties, and so on. (Diass, J. O. et al. Organometallics (2006)
5:1188-1198; Showell, G. A. et al. Bioorganic & Medicinal
Chemistry Letters (2006) 16:2555-2558).
[0133] It is understood that substituents and substitution patterns
on the compounds of the instant invention can be selected by one of
ordinary skill in the art to provide compounds that are chemically
stable and that can be readily synthesized by techniques known in
the art, as well as those methods set forth below, from readily
available starting materials. If a substituent is itself
substituted with more than one group, it is understood that these
multiple groups may be on the same carbon or on different carbons,
so long as a stable structure results. The phrase "optionally
substituted" (with one or more substituents) should be understood
as meaning that the group in question is either unsubstituted or
may be substituted with one or more substituents.
[0134] Furthermore, compounds of the present invention may exist in
amorphous form and/or one or more crystalline forms, and as such
all amorphous and crystalline forms and mixtures thereof of the
compounds of Formula I are intended to be included within the scope
of the present invention. In addition, some of the compounds of the
instant invention may form solvates with water (i.e., a hydrate) or
common organic solvents. Such solvates and hydrates, particularly
the pharmaceutically acceptable solvates and hydrates, of the
instant compounds are likewise encompassed within the scope of this
invention, along with un-solvated and anhydrous forms.
[0135] Reference to the compounds of this invention as those of a
specific formula or embodiment, e.g., Formula I or any other
generic structural formula or specific compound described or
claimed herein, is intended to encompass the specific compound or
compounds falling within the scope of the formula or embodiment,
including salts thereof, particularly pharmaceutically acceptable
salts, solvates of such compounds and solvated salt forms thereof,
where such forms are possible unless specified otherwise.
[0136] Also, in the case of a carboxylic acid (--COOH) or alcohol
group being present in the compounds of the present invention,
pharmaceutically acceptable esters of carboxylic acid derivatives,
such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of
alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl,
can be employed. Included are those esters and acyl groups known in
the art for modifying the solubility or hydrolysis characteristics
for use as sustained-release or prodrug formulations.
[0137] If the compounds of Formula I simultaneously contain acidic
and basic groups in the molecule the invention also includes, in
addition to the salt forms mentioned, inner salts or betaines
(zwitterions). Salts can be obtained from the compounds of Formula
I by customary methods which are known to the person skilled in the
art, for example by combination with an organic or inorganic acid
or base in a solvent or dispersant, or by anion exchange or cation
exchange from other salts. The present invention also includes all
salts of the compounds of Formula I which, owing to low
physiological compatibility, are not directly suitable for use in
pharmaceuticals but which can be used, for example, as
intermediates for chemical reactions or for the preparation of
pharmaceutically acceptable salts.
[0138] Any pharmaceutically acceptable pro-drug modification of a
compound of this invention which results in conversion in vivo to a
compound within the scope of this invention is also within the
scope of this invention. For example, esters can optionally be made
by esterification of an available carboxylic acid group or by
formation of an ester on an available hydroxy group in a compound.
Similarly, labile amides can be made. Pharmaceutically acceptable
esters or amides of the compounds of this invention may be prepared
to act as pro-drugs which can be hydrolyzed back to an acid (or
--COO.sup.- depending on the pH of the fluid or tissue where
conversion takes place) or hydroxy form particularly in vivo and as
such are encompassed within the scope of this invention. Examples
of pharmaceutically acceptable pro-drug modifications include, but
are not limited to, --C.sub.1-6alkyl esters and --C.sub.1-6alkyl
substituted with phenyl esters.
[0139] Accordingly, the compounds within the generic structural
formulas, embodiments and specific compounds described and claimed
herein encompass salts, all possible stereoisomers and tautomers,
physical forms (e.g., amorphous and crystalline forms), solvate and
hydrate forms thereof and any combination of these forms, as well
as the salts thereof, pro-drug forms thereof, and salts of pro-drug
forms thereof, where such forms are possible unless specified
otherwise.
[0140] Except where noted herein, "alkyl" is intended to include
both branched- and straight-chain saturated aliphatic hydrocarbon
groups having the specified number of carbon atoms. Commonly used
abbreviations for alkyl groups are used throughout the
specification, e.g., methyl may be represented by conventional
abbreviations including "Me" or CH.sub.3 or a symbol that is an
extended bond as the terminal group, e.g.
##STR00017##
ethyl may be represented by "Et" or CH.sub.2CH.sub.3, propyl may be
represented by "Pr" or CH.sub.2CH.sub.2CH.sub.3, butyl may be
represented by "Bu" or CH.sub.2CH.sub.2CH.sub.2CH.sub.3, etc.
"C.sub.1-4 alkyl" (or "C.sub.1-C.sub.4 alkyl") for example, means
linear or branched chain alkyl groups, including all isomers,
having the specified number of carbon atoms. For example, the
structures
##STR00018##
have equivalent meanings. C.sub.1-4 alkyl includes n-, iso-, sec-
and t-butyl, n- and isopropyl, ethyl and methyl. If no number is
specified, 1-4 carbon atoms are intended for linear or branched
alkyl groups.
[0141] Also, in the case of a carboxylic acid (--COOH) or alcohol
group being present in the compounds of the present invention,
pharmaceutically acceptable esters of carboxylic acid derivatives,
such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of
alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl,
can be employed. Included are those esters and acyl groups known in
the art for modifying the solubility or hydrolysis characteristics
for use as sustained-release or prodrug formulations.
[0142] If the compounds of Formula I simultaneously contain acidic
and basic groups in the molecule the invention also includes, in
addition to the salt forms mentioned, inner salts or betaines
(zwitterions). Salts can be obtained from the compounds of Formula
I by customary methods which are known to the person skilled in the
art, for example by combination with an organic or inorganic acid
or base in a solvent or dispersant, or by anion exchange or cation
exchange from other salts. The present invention also includes all
salts of the compounds of Formula I which, owing to low
physiological compatibility, are not directly suitable for use in
pharmaceuticals but which can be used, for example, as
intermediates for chemical reactions or for the preparation of
physiologically acceptable salts.
[0143] Any pharmaceutically acceptable pro-drug modification of a
compound of this invention which results in conversion in vivo to a
compound within the scope of this invention is also within the
scope of this invention. For example, esters can optionally be made
by esterification of an available carboxylic acid group or by
formation of an ester on an available hydroxy group in a compound.
Similarly, labile amides can be made. Pharmaceutically acceptable
esters or amides of the compounds of this invention may be prepared
to act as pro-drugs which can be hydrolyzed back to an acid (or
--COO.sup.- depending on the pH of the fluid or tissue where
conversion takes place) or hydroxy form particularly in vivo and as
such are encompassed within the scope of this invention. Examples
of pharmaceutically acceptable pro-drug modifications include, but
are not limited to, --C.sub.1-6alkyl esters and --C.sub.1-6alkyl
substituted with phenyl esters.
[0144] Accordingly, the compounds within the generic structural
formulas, embodiments and specific compounds described and claimed
herein encompass salts, all possible stereoisomers and tautomers,
physical forms (e.g., amorphous and crystalline forms), solvate and
hydrate forms thereof and any combination of these forms, as well
as the salts thereof, pro-drug forms thereof, and salts of pro-drug
forms thereof, where such forms are possible unless specified
otherwise.
[0145] When any variable occurs more than one time in any
constituent or in formula I, its definition on each occurrence is
independent of its definition at every other occurrence. Also,
combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds.
[0146] Except where noted herein, "alkanol" is intended to include
aliphatic alcohols having the specified number of carbon atoms,
such as methanol, ethanol, propanol, etc., where the --OH group is
attached at any aliphatic carbon, e.g., propan-1-ol, propan-2-ol,
etc.
[0147] Except where noted herein, alkyl groups may be
unsubstituted, or substituted with 1 to 3 substituents on any one
or more carbon atoms, with halogen, C.sub.1-C.sub.20 alkyl,
CF.sub.3, NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl).sub.2, NO.sub.2, oxo, CN, N.sub.3, --OH,
--O(C.sub.1-C.sub.6 alkyl), C.sub.3-C.sub.10 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, (C.sub.1-C.sub.6
alkyl)S(O).sub.0-2--, HS(O).sub.0-2--, (C.sub.1-C.sub.6
alkyl)S(O).sub.0-2(C.sub.1-C.sub.6 alkyl)-,
HS(O).sub.0-2(C.sub.1-C.sub.6 alkyl)-, (C.sub.0-C.sub.6
alkyl)C(O)NH--, H.sub.2N--C(NH)--, --O(C.sub.1-C.sub.6
alkyl)CF.sub.3, HC(O)--, (C.sub.1-C.sub.6 alkyl)C(O)--, HOC(O)--,
(C.sub.1-C.sub.6 alkyl)OC(O)--, HO(C.sub.1-C.sub.6 alkyl)-,
(C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl)-, (C.sub.1-C.sub.6
alkyl)C(O).sub.1-2(C.sub.1-C.sub.6 alkyl)-,
HC(O).sub.1-2(C.sub.1-C.sub.6 alkyl)-, (C.sub.1-C.sub.6
alkyl)C(O).sub.1-2--, HOC(O)NH--, (C.sub.1-C.sub.6 alkyl)OC(O)NH--,
aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl,
halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl,
cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl, where
such substitution results in formation of a stable compound.
[0148] Except where noted, the term "halogen" means fluorine,
chlorine, bromine or iodine.
[0149] Except where noted, the term "heterocycle" refers to a
stable 4- to 7-membered mono-cyclic or stable 7- to 12-membered
bicyclic or stable 12- to 14-membered tricyclic
heteroatom-containing ring system unsubstituted or substituted with
C.sub.1-4 alkyl or halogen, any ring of which may be saturated or
unsaturated, and which consists of carbon atoms and from one to
four heteroatoms independently selected from the group consisting
of N, O and S, and wherein the nitrogen and sulfur heteroatoms may
optionally be oxidized, and the nitrogen heteroatom may optionally
be quaternized, and including any bicyclic group in which any of
the above-defined heterocyclic rings is fused to a benzene ring.
Especially useful are rings containing one oxygen or sulfur, one to
four nitrogen atoms, or one oxygen or sulfur combined with one or
two nitrogen atoms. The heterocyclic ring may be attached at any
heteroatom or carbon atom which results in the creation of a stable
structure. Examples of such heterocyclic groups include
piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,
imidazolinyl, imidazolidinyl, pyridyl, pyridyl N-oxide, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl,
isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,
isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl,
isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl,
benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl,
tetrahydropyranyl, tetrazole, thienyl, benzothienyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl
sulfone, and oxadiazolyl. Morpholino is the same as
morpholinyl.
[0150] Except where noted herein, the term "heteroaryl" refers to a
monocyclic unsaturated heterocycle having a specified number of
atom members (e.g., 4, 5, 6 or 7-membered), including a specified
number of heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms independently
selected from N, O or S), or a bicyclic unsaturated ring system
having a specified number of atom members (e.g., 7, 8, 9, 10, 11 or
12-membered) including a specified number of heteroatoms (e.g., 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 heteroatoms independently selected
from N, S or O) or a tricyclic unsaturated ring system having a
specified number of atom members (e.g., 12-, 13- or 14-membered)
including a specified number of heteroatoms (e.g., 1, 2, 3, 4, 5,
6, 7, 8, 9 or 10 heteroatoms independently selected from N, S or O)
e.g., 5-membered rings containing one nitrogen (pyrrole), one
oxygen (furan) or one sulfur (thiophene) atom, 5-membered rings
containing one nitrogen and one sulfur (thiazole) atom, 5-membered
rings containing one nitrogen and one oxygen (oxazole or isoxazole)
atom, 5-membered rings containing two nitrogen (imidazole or
pyrazole) atoms, five-membered aromatic rings containing three
nitrogen atoms, five-membered aromatic rings containing one oxygen,
one nitrogen or one sulfur atom, five-membered aromatic rings
containing two heteroatoms independently selected from oxygen,
nitrogen and sulfur, 6-membered rings containing one nitrogen
(pyridine), or one oxygen (pyran) atom, 6-membered rings containing
two nitrogen (pyrazine, pyrimidine, or pyridazine) atoms,
6-membered rings containing three nitrogen (triazine) atoms, a
tetrazolyl ring; a thiazinyl ring; or coumarinyl. Examples of such
ring systems are furanyl, thienyl, pyrrolyl, pyridinyl,
pyrimidinyl, indolyl, imidazolyl, triazinyl, thiazolyl,
isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl, oxadiazolyl,
triazolyl and isoxazolyl.
[0151] The term "saturated heterocycle" refers to a saturated
monocyclic 5- to 8-membered ring having 1-4 heteroatoms selected
from N, O and S, or a 7- to 12-membered saturated bicyclic ring
system having 1-6 heteroatoms selected from N, O and S, or a 12- to
14-membered ring having 1-4 heteroatoms selected from N, O and S.
Representative examples include piperidinyl, piperazinyl, azepanyl,
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,
isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).
[0152] Except where noted herein, the term "carbocycle" (and
variations thereof such as "carbocyclic" or "carbocyclyl") as used
herein, unless otherwise indicated, refers to a C.sub.3 to C.sub.8
monocyclic saturated or unsaturated ring, e.g., C.sub.3-8
monocyclic carbocycle, or a C.sub.9 to C.sub.12 bicyclic saturated
or unsaturated ring, e.g., C.sub.9-12 bicyclic carbocycle. The
carbocycle may be attached to the rest of the molecule at any
carbon atom which results in a stable compound. Saturated
carbocyclic rings include, for example, "cycloalkyl" rings, e.g.,
cyclopropyl, cyclobutyl, etc. Unsaturated carbocyclic rings
include, for example, "aryl" rings. Unsturated bicyclic carbocyclic
ring systems include fused ring systems where all ring system
members are carbon atoms and where at least one of the fused rings
is not saturated.
[0153] Except where noted, the term "aryl" refers to a stable 6- to
10-membered mono- or bicyclic ring system such as phenyl, or
naphthyl. The aryl ring can be unsubstituted or substituted with
one or more of C.sub.1-4 alkyl, hydroxyl, alkoxy, halogen, or
amino.
[0154] "Celite.RTM." (Fluka) diatomite is diatomaceous earth, and
can be referred to as "celite".
[0155] Except where noted herein, aryl groups and carbocycle groups
may be unsubstituted, or substituted on any one or more carbon
atoms, with halogen, C.sub.1-C.sub.20 alkyl, CF.sub.3, NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
NO.sub.2, oxo, CN, N.sub.3, --OH, --O(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.10 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, HS(O).sub.0-2--, (C.sub.1-C.sub.6
alkyl)S(O).sub.0-2--, (C.sub.1-C.sub.6
alkyl)S(O).sub.0-2(C.sub.1-C.sub.6 alkyl)-,
HS(O).sub.0-2(C.sub.1-C.sub.6 alkyl)-, (C.sub.1-C.sub.6
alkyl)S(O).sub.0-2, (C.sub.1-C.sub.6 alkyl)C(O)NH--, HC(O)NH--,
H.sub.2N--C(NH)--, --O(C.sub.1-C.sub.6 alkyl)CF.sub.3,
(C.sub.1-C.sub.6 alkyl)C(O)--, HC(O)--, (C.sub.1-C.sub.6
alkyl)OC(O)--, HOC(O)--, (C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6
alkyl)-, HO(C.sub.1-C.sub.6 alkyl)-, (C.sub.1-C.sub.6
alkyl)C(O).sub.1-2(C.sub.1-C.sub.6 alkyl)-, (C.sub.1-C.sub.6
alkyl)C(O).sub.1-2--, HC(O).sub.1-2(C.sub.1-C.sub.6 alkyl)-,
(C.sub.1-C.sub.6 alkyl)OC(O)NH--, HOC(O)NH--, --P(O)(OH).sub.2,
aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl,
halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl,
cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl, where
such substitution results in formation of a stable compound.
[0156] Except where noted herein, heterocycles may be
unsubstituted, or substituted on any one or more carbon atoms, with
halogen, C.sub.1-C.sub.20 alkyl, CF.sub.3, NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
NO.sub.2, oxo, CN, N.sub.3, --OH, --O(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.10 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, (C.sub.1-C.sub.6 alkyl)S(O).sub.0-2--,
HS(O).sub.0-2--, (C.sub.1-C.sub.6
alkyl)S(O).sub.0-2(C.sub.1-C.sub.6 alkyl)-,
HS(O).sub.0-2(C.sub.1-C.sub.6 alkyl)-, (C.sub.1-C.sub.6
alkyl)S(O).sub.0-2--, (C.sub.1-C.sub.6 alkyl)C(O)NH--, HC(O)NH--,
H.sub.2N--C(NH)--, --O(C.sub.1-C.sub.6 alkyl)CF.sub.3, HC(O)--,
(C.sub.1-C.sub.6 alkyl)C(O)--, (C.sub.1-C.sub.6 alkyl)OC(O)--,
HOC(O)--, (C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl)-,
HO(C.sub.1-C.sub.6 alkyl)-, (C.sub.1-C.sub.6 alkyl)O--,
(C.sub.1-C.sub.6 alkyl)C(O).sub.1-2(C.sub.1-C.sub.6 alkyl)-,
HC(O).sub.1-2(C.sub.1-C.sub.6 alkyl)-, (C.sub.1-C.sub.6
alkyl)C(O).sub.1-2, (C.sub.1-C.sub.6 alkyl)OC(O)NH--, HOC(O)NH--,
silyl groups (including trimethylsilyl, tetramethylsilyl, or
supersilyl groups such as tri(trimethylsilyl)silyl or a silicon
group connected to tert butyl groups), aryl, aralkyl, heterocycle,
heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle,
halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl,
cyano-heterocycle or cyano-heterocyclylalkyl, or independently or
additionally substituted with 1 substituent on any one or more
nitrogen atoms, with C.sub.1-C.sub.20 alkyl, oxo, C.sub.3-C.sub.10
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl,
--C(O)C.sub.1-6 alkyl, --C(O)NHC.sub.1-C.sub.6 alkyl, --C(O)
NH.sub.2, --C.sub.1-C.sub.6 alkylC(O)NH.sub.2, --C.sub.1-C.sub.6
alkylOC(O)NH.sub.2, or independently or additionally substituted
with 1 substituent on any one or more sulfur atoms, with
C.sub.1-C.sub.20 alkyl, oxo, C.sub.3-C.sub.10 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, where such
substitution results in formation of a stable compound.
[0157] Except where noted herein, structures containing substituent
variables such as variable "R" below:
##STR00019##
which are depicted as not being attached to any one particular
bicyclic ring carbon atom, represent structures in which the
variable can be optionally attached to any bicyclic ring carbon
atom. For example, variable R shown in the above structure can be
attached to any one of 6 bicyclic ring carbon atoms i, ii, iii, iv,
v or vi.
[0158] Except where noted herein, bicyclic ring systems include
fused ring systems, where two rings share two atoms, and spiro ring
systems, where two rings share one atom.
[0159] The invention also includes derivatives of the compounds of
Formula I, acting as prodrugs and solvates. Prodrugs, following
administration to the patient, are converted in the body by normal
metabolic or chemical processes, such as through hydrolysis in the
blood, to the compound of Formula 1. Such prodrugs include those
that demonstrate enhanced bioavailability, tissue specificity,
and/or cellular delivery, to improve drug absorption of the
compound of Formula I. The effect of such prodrugs may result from
modification of physicochemical properties such as lipophilicity,
molecular weight, charge, and other physicochemical properties that
determine the permeation properties of the drug.
[0160] The preparation of pharmaceutically acceptable salts from
compounds of the Formula I capable of salt formation, including
their stereoisomeric forms is carried out in a manner known per se.
With basic reagents such as hydroxides, carbonates,
hydrogencarbonates, alkoxides and ammonia or organic bases, for
example, trimethyl- or triethylamine, ethanolamine, diethanolamine
or triethanolamine, trometamol or alternatively basic amino acids,
for example lysine, ornithine or arginine, the compounds of the
Formula I form stable alkali metal, alkaline earth metal or
optionally substituted ammonium salts. If the compounds of the
Formula I have basic groups, stable acid addition salts can also be
prepared using strong acids. For this, inorganic and organic acids
such as hydrochloric, hydrobromic, sulfuric, hemisulfuric,
phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic,
4-bromobenzenesulfonic, cyclohexylamidosulfonic,
trifluoromethylsulfonic, 2-hydroxyethanesulfonic, acetic, oxalic,
tartaric, succinic, glycerolphosphoric, lactic, malic, adipic,
citric, fumaric, maleic, gluconic, glucuronic, palmitic or
trifluoroacetic acid are suitable.
[0161] The invention also relates to medicaments containing at
least one compound of the Formula I and/or of a pharmaceutically
acceptable salt of the compound of the Formula I and/or an
optionally stereoisomeric form of the compound of the Formula I or
a pharmaceutically acceptable salt of the stereoisomeric form of
the compound of Formula I, together with a pharmaceutically
suitable and pharmaceutically acceptable vehicle, additive and/or
other active substances and auxiliaries.
[0162] Anticoagulant therapy is indicated for the treatment and
prevention of a variety of thrombotic conditions, particularly
coronary artery and cerebrovascular disease. Those experienced in
this field are readily aware of the circumstances requiring
anticoagulant therapy. The term "patient" used herein is taken to
mean mammals such as primates, humans, sheep, horses, cattle, pigs,
dogs, cats, rats, and mice.
[0163] Factor XIa or dual Factor XIa/plasma kallikrein inhibition
are useful not only in the anticoagulant therapy of individuals
having thrombotic conditions, but are useful whenever inhibition of
blood coagulation is required such as to prevent coagulation of
stored whole blood and to prevent coagulation in other biological
samples for testing or storage. Thus, the Factor XIa or dual Factor
XIa/plasma kallikrein inhibitors can be added to or contacted with
any medium containing or suspected of containing thrombin and in
which it is desired that blood coagulation be inhibited, e.g., when
contacting the mammal's blood with material selected from the group
consisting of vascular grafts, stents, orthopedic prosthesis,
cardiac prosthesis, and extracorporeal circulation systems.
[0164] Compounds of the invention may be useful for treating or
preventing venous thromboembolism (e.g., obstruction or occlusion
of a vein by a detached thrombus; obstruction or occlusion of a
lung artery by a detached thrombus), cardiogenic thromboembolism
(e.g., obstruction or occlusion of the heart by a detached
thrombus), arterial thrombosis (e.g., formation of a thrombus
within an artery that may cause infarction of tissue supplied by
the artery), atherosclerosis (e.g., arteriosclerosis characterized
by irregularly distributed lipid deposits) in mammals, and for
lowering the propensity of devices that come into contact with
blood to clot blood.
[0165] Examples of venous thromboembolism which may be treated or
prevented with compounds of the invention include obstruction of a
vein, obstruction of a lung artery (pulmonary embolism), deep vein
thrombosis, thrombosis associated with cancer and cancer
chemotherapy, thrombosis inherited with thrombophilic diseases such
as Protein C deficiency, Protein S deficiency, antithrombin III
deficiency, and Factor V Leiden, and thrombosis resulting from
acquired thrombophilic disorders such as systemic lupus
erythematosus (inflammatory connective tissue disease). Also with
regard to venous thromboembolism, compounds of the invention may be
useful for maintaining patency of indwelling catheters.
[0166] Examples of cardiogenic thromboembolism which may be treated
or prevented with compounds of the invention include thromboembolic
stroke (detached thrombus causing neurological affliction related
to impaired cerebral blood supply), cardiogenic thromboembolism
associated with atrial fibrillation (rapid, irregular twitching of
upper heart chamber muscular fibrils), cardiogenic thromboembolism
associated with prosthetic heart valves such as mechanical heart
valves, and cardiogenic thromboembolism associated with heart
disease.
[0167] Examples of arterial thrombosis include unstable angina
(severe constrictive pain in chest of coronary origin), myocardial
infarction (heart muscle cell death resulting from insufficient
blood supply), ischemic heart disease (local anemia due to
obstruction (such as by arterial narrowing) of blood supply),
reocclusion during or after percutaneous transluminal coronary
angioplasty, restenosis after percutaneous transluminal coronary
angioplasty, occlusion of coronary artery bypass grafts, and
occlusive cerebrovascular disease. Also with regard to arterial
thrombosis, compounds of the invention may be useful for
maintaining patency in arteriovenous cannulas.
[0168] Examples of atherosclerosis include arteriosclerosis.
[0169] The compounds of the invention may also be kallikrein
inhibitors and especially useful for treatment of hereditary
angioedema.
[0170] Examples of devices that come into contact with blood
include vascular grafts, stents, orthopedic prosthesis, cardiac
prosthesis, and extracorporeal circulation systems.
[0171] The medicaments according to the invention can be
administered by oral, inhalative, rectal or transdermal
administration or by subcutaneous, intraarticular, intraperitoneal
or intravenous injection. Oral administration is preferred. Coating
of stents with compounds of the Formula (I) and other surfaces
which come into contact with blood in the body is possible.
[0172] The invention also relates to a process for the production
of a medicament, which comprises bringing at least one compound of
the Formula (I) into a suitable administration form using a
pharmaceutically suitable and pharmaceutically acceptable carrier
and optionally further suitable active substances, additives or
auxiliaries.
[0173] Suitable solid or galenical preparation forms are, for
example, granules, powders, coated tablets, tablets,
(micro)capsules, suppositories, syrups, juices, suspensions,
emulsions, drops or injectable solutions and preparations having
prolonged release of active substance, in whose preparation
customary excipients such as vehicles, disintegrants, binders,
coating agents, swelling agents, glidants or lubricants,
flavorings, sweeteners and solubilizers are used. Frequently used
auxiliaries which may be mentioned are magnesium carbonate,
titanium dioxide, lactose, mannitol and other sugars, talc,
lactose, gelatin, starch, cellulose and its derivatives, animal and
plant oils such as cod liver oil, sunflower, peanut or sesame oil,
polyethylene glycol and solvents such as, for example, sterile
water and mono- or polyhydric alcohols such as glycerol.
[0174] The dosage regimen utilizing the Factor XIa inhibitors or
dual Factor XIa/plasma kallikrein inhibitors is selected in
accordance with a variety of factors including type, species, age,
weight, sex and medical condition of the patient; the severity of
the condition to be treated; the route of administration; the renal
and hepatic function of the patient; and the particular compound or
salt thereof employed. An ordinarily skilled physician or
veterinarian can readily determine and prescribe the effective
amount of the drug required to prevent, counter, or arrest the
progress of the condition.
[0175] Oral dosages of the Factor XIa inhibitors or dual Factor
XIa/plasma kallikrein inhibitors, when used for the indicated
effects, will range between about 0.01 mg per kg of body weight per
day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5
mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably
0.1-0.5 mg/kg/day (unless specified otherwise, amounts of active
ingredients are on free base basis). For example, an 80 kg patient
would receive between about 0.8 mg/day and 2.4 g/day, preferably
2-600 mg/day, more preferably 8-200 mg/day, and most preferably
8-40 mg/kg/day. A suitably prepared medicament for once a day
administration would thus contain between 0.8 mg and 2.4 g,
preferably between 2 mg and 600 mg, more preferably between 8 mg
and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg, 10 mg,
20 mg and 40 mg. Advantageously, the Factor XIa inhibitors may be
administered in divided doses of two, three, or four times daily.
For administration twice a day, a suitably prepared medicament
would contain between 0.4 mg and 4 g, preferably between 1 mg and
300 mg, more preferably between 4 mg and 100 mg, and most
preferably 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg.
[0176] Intravenously, the patient would receive the active
ingredient in quantities sufficient to deliver between 0.025-7.5
mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably
0.1-0.5 mg/kg/day. Such quantities may be administered in a number
of suitable ways, e.g. large volumes of low concentrations of
active ingredient during one extended period of time or several
times a day, low volumes of high concentrations of active
ingredient during a short period of time, e.g. once a day.
Typically, a conventional intravenous formulation may be prepared
which contains a concentration of active ingredient of between
about 0.01-1.0 mg/mL, e.g. 0.1 mg/mL, 0.3 mg/mL, and 0.6 mg/mL, and
administered in amounts per day of between 0.01 mL/kg patient
weight and 10.0 mL/kg patient weight, e.g. 0.1 mL/kg, 0.2 mL/kg,
0.5 mL/kg. In one example, an 80 kg patient, receiving 8 mL twice a
day of an intravenous formulation having a concentration of active
ingredient of 0.5 mg/mL, receives 8 mg of active ingredient per
day. Glucuronic acid, L-lactic acid, acetic acid, citric acid or
any pharmaceutically acceptable acid/conjugate base with reasonable
buffering capacity in the pH range acceptable for intravenous
administration may be used as buffers. The choice of appropriate
buffer and pH of a formulation, depending on solubility of the drug
to be administered, is readily made by a person having ordinary
skill in the art.
[0177] Compounds of the Formula I can be administered both as a
monotherapy and in combination with other therapeutic agents,
including antithrombotics (anticoagulants and platelet aggregation
inhibitors), thrombolytics (plasminogen activators), other
profibrinolytically active substances, hypotensives, blood sugar
regulators, lipid-lowering agents and antiarrhythmics.
[0178] The Factor XIa inhibitors or dual Factor XIa/plasma
kallikrein inhibitors can also be co-administered with suitable
anticoagulants, including, but not limited to, other Factor XIa
inhibitors, thrombin inhibitors, thrombin receptor antagonists,
Factor VIIa inhibitors, Factor Xa inhibitors, Factor IXa
inhibitors, Factor XIIa inhibitors, adenosine diphosphate
antiplatelet agents (e.g., P2Y12 antagonists), fibrinogen receptor
antagonists (e.g. to treat or prevent unstable angina or to prevent
reocclusion after angioplasty and restenosis), other anticoagulants
such as aspirin, and thrombolytic agents such as plasminogen
activators or streptokinase to achieve synergistic effects in the
treatment of various vascular pathologies. Such anticoagulants
include, for example, apixaban, dabigatran, cangrelor, ticagrelor,
vorapaxar, clopidogrel, edoxaban, mipomersen, prasugrel,
rivaroxaban, and semuloparin. For example, patients suffering from
coronary artery disease, and patients subjected to angioplasty
procedures, would benefit from coadministration of fibrinogen
receptor antagonists and thrombin inhibitors. Factor XIa inhibitors
may be administered first following thrombus formation, and tissue
plasminogen activator or other plasminogen activator is
administered thereafter.
[0179] Alternatively or additionally, one or more additional
pharmacologically active agents may be administered in combination
with a compound of the invention. The additional active agent (or
agents) is intended to mean a pharmaceutically active agent (or
agents) that is active in the body, including pro-drugs that
convert to pharmaceutically active form after administration, which
is different from the compound of the invention, and also includes
free-acid, free-base and pharmaceutically acceptable salts of said
additional active agents when such forms are sold commercially or
are otherwise chemically possible. Generally, any suitable
additional active agent or agents, including but not limited to
anti-hypertensive agents, additional diuretics,
anti-atherosclerotic agents such as a lipid modifying compound,
anti-diabetic agents and/or anti-obesity agents may be used in any
combination with the compound of the invention in a single dosage
formulation (a fixed dose drug combination), or may be administered
to the patient in one or more separate dosage formulations which
allows for concurrent or sequential administration of the active
agents (co-administration of the separate active agents). Examples
of additional active agents which may be employed include but are
not limited to angiotensin converting enzyme inhibitors (e.g.,
alacepril, benazepril, captopril, ceronapril, cilazapril, delapril,
enalapril, enalaprilat, fosinopril, imidapril, lisinopril,
moveltipril, perindopril, quinapril, ramipril, spirapril,
temocapril, or trandolapril); angiotensin II receptor antagonists
also known as angiotensin receptor blockers or ARBs, which may be
in free-base, free-acid, salt or pro-drug form, such as azilsartan,
e.g., azilsartan medoxomil potassium (EDARBI.RTM.), candesartan,
e.g., candesartan cilexetil (ATACAND.RTM.), eprosartan, e.g.,
eprosartan mesylate (TEVETAN.RTM.), irbesartan (AVAPRO.RTM.),
losartan, e.g., losartan potassium (COZAAR.RTM.), olmesartan, e.g.,
olmesartan medoximil (BENICAR.RTM.), telmisartan (MICARDIS.RTM.),
valsartan (DIOVAN.RTM.), and any of these drugs used in combination
with a thiazide-like diuretic such as hydrochlorothiazide (e.g.,
HYZAAR.RTM., DIOVAN HCT.RTM., ATACAND HCT.RTM.), etc.); potassium
sparing diuretics such as amiloride HCl, spironolactone,
epleranone, triamterene, each with or without HCTZ; neutral
endopeptidase inhibitors (e.g., thiorphan and phosphoramidon);
aldosterone antagonists; aldosterone synthase inhibitors; renin
inhibitors; enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES
8891; SQ 34017; aliskiren
(2(S),4(S),5(S),7(S)--N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,-
7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamid
hemifumarate) SPP600, SPP630 and SPP635); endothelin receptor
antagonists; vasodilators (e.g. nitroprusside); calcium channel
blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem,
gallopamil, niludipine, nimodipine, nicardipine); potassium channel
activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil,
aprilkalim, loprazolam); sympatholitics; beta-adrenergic blocking
drugs (e.g., acebutolol, atenolol, betaxolol, bisoprolol,
carvedilol, metoprolol, metoprolol tartate, nadolol, propranolol,
sotalol, timolol); alpha adrenergic blocking drugs (e.g.,
doxazosin, prazosin or alpha methyldopa); central alpha adrenergic
agonists; peripheral vasodilators (e.g. hydralazine); lipid
lowering agents, e.g., HMG-CoA reductase inhibitors such as
simvastatin and lovastatin which are marketed as ZOCOR.RTM. and
MEVACOR.RTM. in lactone pro-drug form and function as inhibitors
after administration, and pharmaceutically acceptable salts of
dihydroxy open ring acid HMG-CoA reductase inhibitors such as
atorvastatin (particularly the calcium salt sold in LIPITOR.RTM.),
rosuvastatin (particularly the calcium salt sold in CRESTOR.RTM.),
pravastatin (particularly the sodium salt sold in PRAVACHOL.RTM.),
and fluvastatin (particularly the sodium salt sold in LESCOL.RTM.);
a cholesterol absorption inhibitor such as ezetimibe (ZETIA.RTM.),
and ezetimibe in combination with any other lipid lowering agents
such as the HMG-CoA reductase inhibitors noted above and
particularly with simvastatin (VYTORIN.RTM.) or with atorvastatin
calcium; niacin in immediate-release or controlled release forms,
and particularly niacin in combination with a DP antagonist such as
laropiprant and/or with an HMG-CoA reductase inhibitor; niacin
receptor agonists such as acipimox and acifran, as well as niacin
receptor partial agonists; metabolic altering agents including
insulin sensitizing agents and related compounds for the treatment
of diabetes such as biguanides (e.g., metformin), meglitinides
(e.g., repaglinide, nateglinide), sulfonylureas (e.g.,
chlorpropamide, glimepiride, glipizide, glyburide, tolazamide,
tolbutamide), thiazolidinediones also referred to as glitazones
(e.g., pioglitazone, rosiglitazone), alpha glucosidase inhibitors
(e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors, (e.g.,
sitagliptin (JANUVIA.RTM.), alogliptin, vildagliptin, saxagliptin,
linagliptin, dutogliptin, gemigliptin), ergot alkaloids (e.g.,
bromocriptine), combination medications such as JANUMET.RTM.
(sitagliptin with metformin), and injectable diabetes medications
such as exenatide and pramlintide acetate; inhibitors of glucose
uptake, such as sodium-glucose transporter (SGLT) inhibitors and
its various isoforms, such as SGLT-1, SGLT-2 (e.g., ASP-1941,
TS-071, BI-10773, tofogliflozin, LX-4211, canagliflozin,
dapagliflozin, ertugliflozin, ipragliflozin and remogliflozin), and
SGLT-3; or with other drugs beneficial for the prevention or the
treatment of the above-mentioned diseases including but not limited
to diazoxide; and including the free-acid, free-base, and
pharmaceutically acceptable salt forms, pro-drug forms, e.g.,
esters, and salts of pro-drugs of the above medicinal agents, where
chemically possible. Trademark names of pharmaceutical drugs noted
above are provided for exemplification of the marketed form of the
active agent(s); such pharmaceutical drugs could be used in a
separate dosage form for concurrent or sequential administration
with a compound of the invention, or the active agent(s) therein
could be used in a fixed dose drug combination including a compound
of the invention.
[0180] Typical doses of Factor XIa inhibitors or Factor XIa/plasma
kallikrein inhibitors of the invention in combination with other
suitable anti-platelet agents, anticoagulation agents, or
thrombolytic agents may be the same as those doses of Factor XIa
inhibitors administered without coadministration of additional
anti-platelet agents, anticoagulation agents, or thrombolytic
agents, or may be substantially less that those doses of thrombin
inhibitors administered without coadministration of additional
anti-platelet agents, anticoagulation agents, or thrombolytic
agents, depending on a patient's therapeutic needs.
[0181] The compounds are administered to a mammal in a
therapeutically effective amount. By "therapeutically effective
amount" it is meant an amount of a compound of the present
invention that, when administered alone or in combination with an
additional therapeutic agent to a mammal, is effective to treat
(i.e. prevent, inhibit or ameliorate) the thromboembolic and/or
inflammatory disease condition or treat the progression of the
disease in a host.
[0182] The compounds of the invention are preferably administered
alone to a mammal in a therapeutically effective amount. However,
the compounds of the invention can also be administered in
combination with an additional therapeutic agent, as defined below,
to a mammal in a therapeutically effective amount. When
administered in a combination, the combination of compounds is
preferably, but not necessarily, a synergistic combination.
Synergy, as described for example by Chou and Talalay, Adv. Enzyme
Regul. 1984, 22, 27-55, occurs when the effect (in this case,
inhibition of the desired target) of the compounds when
administered in combination is greater than the additive effect of
each of the compounds when administered individually as a single
agent. In general, a synergistic effect is most clearly
demonstrated at suboptimal concentrations of the compounds. Synergy
can be in terms of lower cytotoxicity, increased anticoagulant
effect, or some other beneficial effect of the combination compared
with the individual components.
[0183] By "administered in combination" or "combination therapy" it
is meant that the compound of the present invention and one or more
additional therapeutic agents are administered concurrently to the
mammal being treated. When administered in combination each
component may be administered at the same time or sequentially in
any order at different points in time. Thus, each component may be
administered separately but sufficiently closely in time so as to
provide the desired therapeutic effect.
[0184] The present invention is not limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope
of this invention. Indeed, various modifications of the invention
in addition to those shown and described herein will become
apparent to those skilled in the relevant art and are intended to
fall within the scope of the appended claims.
[0185] Abbreviations used herein are as follows:
Boc is tert-butyloxycarbonyl BOP Cl is
bis(2-oxo-3-oxazolidinyl)phosphinic chloride BOP reagent is
benzotriazol-1-yloxy tris(dimethylamino)phosphonium
hexafluorophosphate celite is Celite.RTM. diatomaceous earth DCC is
1,3-dicyclohexylcarbodiimide DCM is dichloromethane DIPEA is
diisopropylethylamine
DMF is N,N-dimethylformamide
[0186] EDC is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride Et is ethyl HATU is
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate HPLC is high performance liquid chromatography
IPA is isopropyl alcohol LCMS is Liquid chromatography mass
spectrometry Me is methyl Ph is phenyl PyBOP is
benzotriaxole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate SFC is supercritical fluid chromatography TEA
is triethylamine TFA is trifluoroacetic acid THF is tetrahydrofuran
WSC HCl is 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide
hydrochloride
[0187] Also, TLC is thin layer chromatography; Ts is tosyl; UV is
ultraviolet; W is watts; wt. % is percentage by weight; .times.g is
times gravity; .alpha..sub.D is the specific rotation of polarized
light at 589 nm; .degree. C. is degrees Celsius; % w/v is
percentage in weight of the former agent relative to the volume of
the latter agent.
Methods for Making the Compounds of Present Invention
General Methods
[0188] The compounds of the present invention can be readily
produced from known compounds or commercially available compounds
by, for example, known processes described in published documents,
and produced by production processes described below. The present
invention is not limited to the production processes described
below. The invention also includes processes for the preparation of
compounds of the invention.
[0189] It should be noted that, when compounds of the present
invention synthesized has a reactive group such as hydroxy group,
amino group, carboxyl group, or thiol group as its substituent,
such group may be adequately protected with a protective group in
each reaction step and the protective group may be removed at an
adequate stage. The process of such introduction and removal of the
protective group may be adequately determined depending on the
group to be protected and the type of the protective group, and
such introduction and removal are conducted, for example, by the
process described in the review section of Greene, T. W., et. al.,
"Protective Groups in Organic Synthesis", 2007, 4th Ed., Wiley, New
York, or Kocienski, P., "Protecting Groups" 1994, Thieme. Unless
otherwise indicated, all variables used in the Schemes below are as
defined above.
##STR00020##
<Step 1-1>
[0190] A compound represented by formula (i-c) can be produced by
allowing 3-bromo-5-fluoropicolinic acid (i-a) to react with a
compound represented by formula (i-b) by a well-known or a process
similar to that described in published documents, for example,
Organic synthesis IV, Acids, amino acids, and peptides, pp.
191-309, 1992, Maruzen Co., Ltd., in the presence of a condensing
agent such as 1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(WSC.HCl or EDC HCl),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), benzotriazol-1-yloxy
tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent),
or bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP--Cl), in a
solvent which is inactive to the reaction, such as a halogenated
solvent, e.g., dichloromethane or chloroform, an ethereal solvent,
e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon
solvent, e.g., toluene or benzene, a polar solvent, e.g.,
N,N-dimethylformamide, or an alcoholic solvent, e.g., methanol,
ethanol, or 2-propanol, in the presence or absence of a base such
as triethylamine or N,N-diisopropylethyl amine at a temperature in
the range of 0.degree. C. to the solvent reflux temperature.
<Step 1-2>
[0191] A compound represented by formula (i-e) can be produced from
the reaction of a compound represented by formula (i-c) and a
compound represented by (i-d) by a well-known or similar process
that is described in published documents, for example, Metal
Catalyzed Cross-Coupling Reactions, 2.sup.nd Edition, 2004,
Wiley-VCH, in the presence of a palladium catalyst such as
tetrakis(triphenylphosphine)palladium(0),
bis(triphenylphosphine)palladium(II) dichloride, or
(1,1'-bis(diphenylphosphino)-ferrocene)palladium(II) dichloride, an
inorganic base such as sodium carbonate, potassium carbonate, or
potassium phosphate. The reaction can be carried out with water or
without water and a solvent which is inactive to the reaction, such
as toluene, N,N-dimethylformamide, dioxane, or a mixed solvent
thereof at a temperature in the range of 90.degree. C. to
120.degree. C. using conventional or microwave heating.
<Step 1-3>
[0192] A compound represented by formula (i-g) can be produced by
allowing a compound represented by formula (i-e) to react with a
compound represented by formula (i-f) by a well-known substitution
reaction under the influence of base such as, potassium phosphate,
cesium carbonate, potassium tert-butoxide, sodium hydride, lithium
hydroxide, sodium hydroxide, potassium hydroxide, lithium
carbonate, sodium carbonate, or potassium carbonate, triethyl
amine, diethylisopropyl amine using a solvent which is inactive to
the reaction, such as an ethereal solvent, e.g., diethyl ether,
tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, polar solvents
such as N,N-dimethylformamide, and dimethyl sulfoxide; or an
aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed
solvent thereof at a temperature in the range of room temperature
to the solvent-reflux temperature.
<Step 1-4>
[0193] A compound represented by formula (i-h) can be produced by
allowing a compound represented by formula (i-g) to react with
hydrogen gas by a well-known or similar process to that described
in published documents, for example, Metal Catalyzed Reactions of
Hydrocarbons, pp. 437-471, 2005, Springer US, in the presence of
hydrogen gas and a catalyst such as platinum (IV) oxide, rhodium on
alumina, rhodium on carbon, Raney nickel, or rhodium (III) oxide,
or mixtures thereof. The reaction can be performed with or without
the addition of an acid such as hydrochloric acid, and it can be
occur in an inert solvent such as methanol, ethanol, 2-propanol, or
water, or mixtures thereof, at room temperature and hydrogen
pressures ranging from atmospheric pressure to 60 psi. The process
as described above can generate a compound represented by formula
(i-f) as a racemic mixture of cis-2,3,5-trisubstituted
piperidines.
<Step 1-5>
[0194] A compound represented by formula (i-j) can be produced by
allowing a compound represented by formula (i-h) to react with a
compound of formula (i-i) by a well-known or similar process to
that described in published documents, for example, Organic
synthesis IV, Acids, amino acids, and peptides, pp. 191-309, 1992,
Maruzen Co., Ltd., in the presence of a condensing agent such as
1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(WSC.HCl or EDC HCl),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), benzotriazol-1-yloxy
tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP--Cl), or
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
(PyBOP) in a solvent which is inactive to the reaction, such as a
halogenated solvent, e.g., dichloromethane or chloroform, an
ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an
aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar
solvent, e.g., N,N-dimethyl-formamide, or an alcoholic solvent,
e.g., methanol, ethanol, or 2-propanol, in the presence or absence
of a base such as triethylamine or N,N-diisopropylethyl amine at a
temperature in the range of 0.degree. C. to the solvent reflux
temperature. The process as described above can generate a compound
of formula (i-h) as a racemic mixture of cis 2,3,5-trisubstituted
piperidines. A compound of formula (i-h) can be obtained as a
single enantiomer using a chiral resolution process such as chiral
preparatory HPLC or chiral supercritical fluid chromatography
(SFC).
##STR00021##
<Step 2-1>
[0195] In the specific case where a compound of formula (i-j)
(Scheme 1) contains a tert-butyl ester group, as represented by a
compound of formula (ii-a), a carboxylic acid compound represented
by formula (ii-b) can be produced following a well-known process or
a process similar to that described in published documents, for
example, Greene, T. W., et. al., Protective Groups in Organic
Synthesis (2007), 4th Ed., in the presence of an acid such as
trifluoroacetic acid, formic acid, hydrochloric acid, or acetic
acid in a solvent which is inactive to the reaction, such as a
halogenated solvent, e.g., dichloromethane or chloroform, or an
ethereal solvent, e.g., dioxane or tetrahydrofuran, at a
temperature in the range of 0.degree. C. to the solvent reflux
temperature. The process as described above can generate a compound
of formula (ii-b) as a racemic mixture of cis 2,3,5-trisubstituted
piperidines. A compound of formula (ii-b) can be obtained as a
single enantiomer using a chiral resolution process such as chiral
preparatory HPLC or chiral supercritical fluid chromatography
(SFC).
##STR00022##
[0196] R.sup.5 and R.sup.5' are independently hydrogen, C.sub.1-6
alkyl, amide, sulfonamide, or form a heterocycle with NH
<Step 3-1>
[0197] A compound represented by formula (iii-c) can be produced by
allowing 3-bromo-5-fluropicolinic acid (iii-a) to react with a
compound represented by formula (iii-b) by a well-known or a
process similar to that described in published documents, for
example, Organic synthesis IV, Acids, amino acids, and peptides,
pp. 191-309, 1992, Maruzen Co., Ltd., in the presence of a
condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(WSC.HCl or EDC HCl),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), benzotriazol-1-yloxy
tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent),
or bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP--Cl), in a
solvent which is inactive to the reaction, such as a halogenated
solvent, e.g., dichloromethane or chloroform, an ethereal solvent,
e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon
solvent, e.g., toluene or benzene, a polar solvent, e.g.,
N,N-dimethylformamide, or an alcoholic solvent, e.g., methanol,
ethanol, or 2-propanol, in the presence or absence of a base such
as triethylamine or N,N-diisopropylethyl amine at a temperature in
the range of 0.degree. C. to the solvent reflux temperature.
<Step 3-2>
[0198] A compound represented by formula (iii-e) can be produced
from the reaction of a compound represented by formula (iii-c) and
a compound represented by (iii-d) by a well-known or similar
process that is described in published documents, for example,
Metal Catalyzed Cross-Coupling Reactions, 2.sup.nd Edition, 2004,
Wiley-VCH, in the presence of a palladium catalyst such as
tetrakis(triphenylphosphine)palladium(0),
bis(triphenylphosphine)palladium(II) dichloride, or
(1,1'-bis(diphenylphosphino)-ferrocene)palladium(II) dichloride, an
inorganic base such as sodium carbonate, potassium carbonate, or
potassium phosphate. The reaction can be carried out with water or
without water and a solvent which is inactive to the reaction, such
as toluene, N,N-dimethylformamide, dioxane, or a mixed solvent
thereof at a temperature in the range of 90.degree. C. to
120.degree. C. using conventional or microwave heating.
<Step 3-3>
[0199] A compound represented by formula (iii-g) can be produced by
allowing a compound represented by formula (iii-e) to react with a
compound represented by formula (iii-f) by a well-known
substitution reaction under the influence of base such as,
potassium phosphate, cesium carbonate, potassium tert-butoxide,
sodium hydride, lithium hydroxide, sodium hydroxide, potassium
hydroxide, lithium carbonate, sodium carbonate, or potassium
carbonate, triethyl amine, diethylisopropyl amine using a solvent
which is inactive to the reaction, such as an ethereal solvent,
e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane,
1,4-dioxane, polar solvents such as N,N-dimethylformamide, and
dimethyl sulfoxide; or an aromatic hydrocarbon solvent, e.g.,
toluene or benzene or a mixed solvent thereof at a temperature in
the range of room temperature to the solvent-reflux
temperature.
<Step 3-4>
[0200] A compound represented by formula (iii-h) can be produced by
allowing a compound represented by formula (iii-g) to react with
hydrogen gas by a well-known or similar process to that described
in published documents, for example, Metal Catalyzed Reactions of
Hydrocarbons, pp. 437-471, 2005, Springer US, in the presence of
hydrogen gas and a catalyst such as platinum (IV) oxide, rhodium on
alumina, rhodium on carbon, Raney nickel, or rhodium (III) oxide,
or mixtures thereof. The reaction can be performed with or without
the addition of an acid such as hydrochloric acid, and it can be
occur in an inert solvent such as methanol, ethanol, 2-propanol, or
water, or mixtures thereof, at room temperature and hydrogen
pressures ranging from atmospheric pressure to 60 psi. The process
as described above can generate a compound represented by formula
(iii-h) as a racemic mixture of cis-2,3,5-trisubstituted
piperidines.
<Step 3-5>
[0201] A compound represented by formula (iii-j) can be produced by
allowing a compound represented by formula (iii-h) to react with a
compound of formula (iii-i) by a well-known or similar process to
that described in published documents, for example, Organic
synthesis IV, Acids, amino acids, and peptides, pp. 191-309, 1992,
Maruzen Co., Ltd., in the presence of a condensing agent such as
1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(WSC.HCl or EDC HCl),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), benzotriazol-1-yloxy
tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP--Cl), or
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
(PyBOP) in a solvent which is inactive to the reaction, such as a
halogenated solvent, e.g., dichloromethane or chloroform, an
ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an
aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar
solvent, e.g., N,N-dimethyl-formamide, or an alcoholic solvent,
e.g., methanol, ethanol, or 2-propanol, in the presence or absence
of a base such as triethylamine or N,N-diisopropylethyl amine at a
temperature in the range of 0.degree. C. to the solvent reflux
temperature. The process as described above can generate a compound
of formula (iii-h) as a racemic mixture of cis 2,3,5-trisubstituted
piperidines. A compound of formula (iii-h) can be obtained as a
single enantiomer using a chiral resolution process such as chiral
preparatory HPLC or chiral supercritical fluid chromatography
(SFC).
##STR00023##
<Step 4-1>
[0202] In the specific case where a compound of formula
(iii-j)(Scheme 3) contains a tert-butyl ester group, as represented
by a compound of formula (iv-a), a carboxylic acid compound
represented by formula (iv-b) can be produced following a
well-known process or a process similar to that described in
published documents, for example, Greene, T. W., et. al.,
Protective Groups in Organic Synthesis (2007), 4th Ed., in the
presence of an acid such as trifluoroacetic acid, formic acid,
hydrochloric acid, or acetic acid in a solvent which is inactive to
the reaction, such as a halogenated solvent, e.g., dichloromethane
or chloroform, or an ethereal solvent, e.g., dioxane or
tetrahydrofuran, at a temperature in the range of 0.degree. C. to
the solvent reflux temperature. The process as described above can
generate a compound of formula (iv-b) as a racemic mixture of cis
2,3,5-trisubstituted piperidines. A compound of formula (iv-b) can
be obtained as a single enantiomer using a chiral resolution
process such as chiral preparatory HPLC or chiral supercritical
fluid chromatography (SFC).
##STR00024## ##STR00025##
<Step 5-1>
[0203] A compound represented by formula (v-c) can be produced by
allowing methyl 3-bromo-5-fluoropicolinate (v-a) to react with a
boronic acid (or corresponding boronate ester) represented by
formula (v-b) by a well-known or similar process that is described
in published documents, for example, Metal Catalyzed Cross-Coupling
Reactions, 2.sup.nd Edition, 2004, Wiley-VCH, in the presence of a
palladium catalyst such as
tetrakis(triphenylphosphine)palladium(0),
bis(triphenylphosphine)palladium(II) dichloride, or
(1,1'-bis(diphenylphosphino)-ferrocene)palladium(II) dichloride, an
inorganic base such as sodium carbonate, potassium carbonate, or
potassium phosphate. The reaction can be carried out with water or
without water and a solvent which is inactive to the reaction, such
as toluene, N,N-dimethylformamide, dioxane, or a mixed solvent
thereof at a temperature in the range of 90.degree. C. to
120.degree. C. using conventional or microwave heating.
<Step 5-2>
[0204] A compound represented by formula (v-f), in which W is a
nitrogen, can be produced from the reaction of a compound
represented by formula (v-c) and a compound represented by (v-d) by
a nucleophilic substitution reaction which is well-known to one
skilled in the art. This reaction may occur in the presence of a
base such as potassium phosphate, cesium carbonate, potassium
tert-butoxide, sodium hydride, lithium hydroxide, sodium hydroxide,
potassium hydroxide, lithium carbonate, sodium carbonate, or
potassium carbonate, triethyl amine or diethylisopropyl amine using
a solvent which is inactive to the reaction, such as an ethereal
solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane,
1,4-dioxane, polar solvents such as N,N-dimethylformamide, and
dimethyl sulfoxide; or an aromatic hydrocarbon solvent, e.g.,
toluene or benzene or a mixed solvent thereof at a temperature in
the range of room temperature to the solvent-reflux temperature.
The reaction may be carried out using conventional heating or
microwave irradiation.
[0205] A compound represented by formula (v-f), in which W is a
carbon, can be produced from the reaction of a compound represented
by formula (v-c) and a boronate ester compound represented by (v-e)
by a Suzuki coupling reaction (Tetrahedron Letters, 2000, vol. 41,
pages 3705-3708). This reaction may be carried out in the presence
of a palladium catalyst such as 1,1'
bis(diphenylphosphino)ferrocene-palladium(II)dichloride and a base
such as potassium carbonate, sodium carbonate, or potassium
phosphate. The reaction may occur in an inert solvent such as
dioxane, THF, or DMF at temperatures in the range of 90.degree. C.
to 120.degree. C. using conventional or microwave heating.
<Step 5-3>
[0206] A compound represented by formula (v-g) can be produced by
allowing a compound represented by formula (v-f) to react with
hydrogen gas by a well-known or similar process to that described
in published documents, for example, Metal Catalyzed Reactions of
Hydrocarbons, pp. 437-471, 2005, Springer US, in the presence of
hydrogen gas and a catalyst such as platinum (IV) oxide, rhodium on
alumina, rhodium on carbon, or rhodium (III) oxide, or mixtures
thereof. The reaction can be performed with or without the addition
of an acid such as hydrochloric acid, and it can occur in an inert
solvent such as methanol, ethanol, 2-propanol, or water, or
mixtures thereof, at room temperature and hydrogen pressures
ranging from atmospheric pressure to 60 psi. The process as
described above can generate a compound represented by formula
(v-g) as a racemic mixture of cis-2,3,5-trisubstituted
piperidines.
<Step 5-4>
[0207] A compound represented by formula (v-h) can be produced by
allowing a compound represented by formula (v-g) to react with
benzyl chloroformate in the presence of an amine base such as
triethylamine or diisopropylethylamine. The reaction may be carried
out in an inert solvent such as dichloromethane at a temperature in
the range of 0.degree. C. and room temperature.
<Step 5-5>
[0208] A compound represented by formula (v-i) can be produced by a
basic hydrolysis reaction, which is well known to those skilled in
the art. The reaction may occur by allowing a compound represented
by formula (v-h) to react with a alkaline hydroxide such as lithium
hydroxide, sodium hydroxide, or potassium hydroxide. The reaction
may be carried out in an inert solvent such as THF with or without
the addition of water and in a temperature in the range of
0.degree. C. and the reflux temperature.
<Step 5-6>
[0209] A compound represented by formula (v-k) may be produced by
allowing the intermediate (v-i) to react with a properly
substituted .alpha.-haloketone (v-j), where X is Cl, Br, or I,
following a well-known process or a process similar to that
described in published documents, for example, Contour-Galcera,
M.-O., Poitout, L.; Moinet, C.; Morgan, B.; Gordon, T.; Roubert,
P.; Thurieau, C. Bioorganic and Medicinal Chemistry Letters, 2001,
Volume 11, Issue 5, pages 741-745, in the presence of a base such
as potassium carbonate, sodium carbonate, cesium carbonate,
triethylamine, or N,N-diisopropylethylamine in a solvent such as
N,N-dimethylformamide, ethanol, methanol, water, or mixtures
thereof, at a temperature between room temperature and 60.degree.
C.
<Step 5-7>
[0210] A compound represented by formula (v-l) may be produced by
allowing a compound of formula (v-k) to react with ammonium acetate
using a process similar to that described in published documents,
for example, Contour-Galcera, M.-O., Poitout, L.; Moinet, C.;
Morgan, B.; Gordon, T.; Roubert, P.; Thurieau, C. Bioorganic and
Medicinal Chemistry Letters, 2001, Volume 11, Issue 5, pages
741-745. This process may occur in an inert solvent such as
toluene, xylenes, or acetic acid, or mixtures thereof, at
temperatures ranging from 110.degree. C. and 150.degree. C. The
reaction can proceed using conventional heating or microwave
irradiation.
<Step 5-8>
[0211] A compound represented by formula (v-m) may be produced by
allowing a compound of formula (v-l) to react with hydrogen gas in
the presence of a catalyst such as palladium on carbon. This
reaction may occur in an inert solvent such as ethyl acetate for
several hours.
<Step 5-9>
[0212] The compound of the invention represented by formula (v-o)
may be produced by allowing a compound of formula (v-m) to react
with a carboxylic acid of formula (v-n) by a well-known or similar
process to that described in published documents, for example,
Organic synthesis IV, Acids, amino acids, and peptides, pp.
191-309, 1992, Maruzen Co., Ltd., in the presence of a condensing
agent such as 1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3'-dimethylamino-propyl)carbodiimide hydrochloride
(WSC.HCl or EDC HCl),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), benzotriazol-1-yloxy
tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP--Cl), or
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
(PyBOP) in a solvent which is inactive to the reaction, such as a
halogenated solvent, e.g., dichloromethane or chloroform, an
ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an
aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar
solvent, e.g., N,N-dimethyl-formamide, or an alcoholic solvent,
e.g., methanol, ethanol, or 2-propanol, in the presence or absence
of a base such as triethylamine or N,N-diisopropylethyl amine at a
temperature in the range of 0.degree. C. to the solvent reflux
temperature.
[0213] The process as described above can generate a compound of
formula (v-o) as a racemic mixture of cis 2,3,5-trisubstituted
piperidines. A compound of formula (v-o) can be obtained as a
single enantiomer using a chiral resolution process such as chiral
preparatory HPLC or chiral supercritical fluid chromatography
(SFC).
[0214] In specific cases in which group Y in compound (v-o)
contains an amine, it may be necessary to deprotect the amine group
using an acid such as trifluoroacetic acid or hydrochloric acid in
order to obtain the final compound of the invention (Greene, T. W.,
et. al., "Protective Groups in Organic Synthesis", 2007, 4th Ed.,
Wiley, New York).
Example 1
4-((3'S,5'S,6'S)-4-Amino-1'-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)ac-
ryloyl)-5'-phenyl-[1,3'-bipiperidine]-6'-carboxamido)benzoic
acid
##STR00026##
[0215] Step 1: tert-Butyl
4-(5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-phenylpicolinamido)
benzoate
##STR00027##
[0217] N,N-Diisopropylethylamine (0.623 ml, 3.57 mmol) was added to
a mixture of tert-butyl piperidin-4-ylcarbamate (715 mg, 3.57 mmol)
and tert-butyl 4-(5-fluoro-3-phenylpicolinamido)benzoate (700 mg,
1.78 mmol) in DMF 10 ml. The mixture was stirred at 150.degree. C.
in a microwave reactor for 2 hours. The mixture was cooled and
diluted with ethyl acetate. The organic phase was washed with
aqueous sodium hydrogen carbonate, filtered, and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (Biotage.RTM. 40M), eluting with
ethyl acetate/isohexane to give tert-butyl
4-(5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-phenylpicolinamido)
benzoate as 880 mg (86%) of a yellow solid. MS (ESI) m/z 573.61
(M+H).
Step 2: tert-Butyl
4-(-4-((tert-butoxycarbonyl)amino)-5'-phenyl-[1,3'-bipiperidine]-6'-carbo-
xamido)benzoate
##STR00028##
[0219] Platinum(IV) oxide (13.5 mg, 0.059 mmol) was added to a
stirred room temperature mixture of tert-butyl
4-(5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-phenylpicolinamido)
benzoate (170 mg, 0.297 mmol) and methanol (15 ml). To this mixture
was added 1 N aqueous HCl (0.6 mL). The reaction was degassed and
then stirred under a hydrogen balloon at room temperature for 12
hours. The reaction mixture was filtered through a celite pad, and
concentrated to dryness. The crude was used without further
purification.
Step 3: tert-Butyl
4-(4-((tert-butoxycarbonyl)amino)-1'-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl-
)phenyl)acryloyl)-5'-phenyl-[1,3'-bipiperidine]-6'-carboxamido)benzoate
##STR00029##
[0221] N,N-Diisopropylethylamine (0.06 ml, 0.352 mmol) was added to
a stirred, room temperature mixture of HATU (134 mg, 0.352 mmol),
tert-butyl
4-(-4-((tert-butoxycarbonyl)amino)-5'-phenyl-[1,3'-bipiperidine]-6'-carbo-
xamido)benzoate (68 mg, 0.117 mmol), and
(E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid (57 mg,
0.228 mmol) in DMF (4 mL) and the mixture was stirred at room
temperature for 4 hours. The mixture was cooled and diluted with
ethyl acetate. The organic phase was washed with aqueous sodium
bicarbonate, dried over MgSO.sub.4, filtered and the solvent was
evaporated under reduced pressure to give a yellow solid. The
residue was purified by column chromatography on silica gel
(Biotage.RTM. 25M) eluting with ethyl acetate/isohexane to give
tert-butyl
4-(4-((tert-butoxycarbonyl)amino)-1'-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl-
)phenyl)acryloyl)-5'-phenyl-[1,3'-bipiperidine]-6'-carboxamido)benzoate
(MS (ESI) m/z 812.37 (M+H).
Step 4:
4-(4-Amino-1'-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl-
)-5'-phenyl-[1,3'-bipiperidine]-6'-carboxamido)benzoic acid
(Example 1)
##STR00030##
[0223] Trifluoroacetic acid (1 ml) was added to a stirred, room
temperature mixture of tert-butyl
4-(4-((tert-butoxycarbonyl)amino)-1'-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl-
)phenyl)acryloyl)-5'-phenyl-[1,3'-bipiperidine]-6'-carboxamido)benzoate
80 mg in DCM (2 ml) and the mixture was stirred at room temperature
for 1 hr. The reaction mixture was concentrated and dissolved in
MeOH and then purified by reverse phase Gilson HPLC (CH3CN/Water)
to give
4-(1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-cyclohexyl-5-
-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid as white
solid. (MS (ESI) m/z 656.65 (M+H).
[0224] The following compounds may be prepared by someone skilled
in the art following a procedure similar to the one described
above. In cases where a chiral non-racemic compound is indicated, a
chiral resolution by supercritical fluid chromatography may be
performed on either the final product or late stage
intermediates.
TABLE-US-00001 LCMS Example Structure IUPAC Name [M + H]+ 2
##STR00031## 4-{[(1-{(2E)-3-[5- chloro-2-(1H-tetrazol-
1-yl)phenyl]prop-2- enoyl}-3-phenyl-5- piperazin-1- ylpiperidin-2-
yl)carbonyl]amino} benzoic acid 641.41 3 ##STR00032##
4-({[4-amino-1'-{(2E)- 3-[5-chloro-2-(1H- tetrazol-1-
yl)phenyl]prop-2- enoyl}-5'-(1- methylethyl)-1,3'- bipiperidin-6'-
yl]carbonyl}amino) benzoic acid 621.54 4 ##STR00033##
4-{[(4-amino-1'-{(2E)- 3-[5-chloro-2-(1H- tetrazol-1-
yl)phenyl]prop-2- enoyl}-5'-cyclopropyl- 1,3'-bipiperidin-6'-
yl)carbonyl]amino} benzoic acid 619.66 5 ##STR00034##
4-{[(4-amino-1'-{(2E)- 3-[5-chloro-2-(1H- tetrazol-1-
yl)phenyl]prop-2- enoyl}-5'-methyl-1,3'- bipiperidin-6'-
yl)carbonyl]amino} benzoic acid 593.58 6 ##STR00035##
4-({[(3'S,5'S,6'S)-4- amino-1'-{(2E)-3-[5- chloro-2-(1H-tetrazol-
1-yl)phenyl]prop-2- enoyl}-5'-phenyl-1,3'- bipiperidin-6'-
yl]carbonyl}amino) benzoic acid 655.42 7 ##STR00036##
4-({[(3'R,5'R,6'R)-4- amino-1'-{(2E)-3-[5- chloro-2-(1H-tetrazol-
1-yl)phenyl]prop-2- enoyl}-5'-phenyl-1,3'- bipiperidin-6'-
yl]carbonyl}amino) benzoic acid 655.42
ExampleS 8-10
4-(4-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamido)-1'-((E)-3-(5--
chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5'-phenyl-[1,3'-bipiperidine]--
6'-carboxamido)benzoic acid (Example 8)
4-((2S,3S,5S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-ph-
enyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid
(Example 9)
4-((2R,3R,5R)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-ph-
enyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid
(Example 10)
##STR00037## ##STR00038##
[0225] Step 1: tert-Butyl
4-(3-bromo-5-fluoropicolinamido)benzoate
##STR00039##
[0227] N,N-Diisopropylethylamine (11.07 ml, 63.4 mmol) was added to
a stirred room temperature mixture of HATU (16 g, 42.3 mmol),
tert-butyl-4-aminobenzoate 6.13 g (31.7 mmol), and
3-bromo-5-fluoropicolinic acid (4.65 g, 21.14 mmol) in DMF 30 ml.
The mixture was stirred at room temperature overnight. The mixture
was cooled and diluted with ethyl acetate. The organic phase was
washed with aqueous sodium hydrogen carbonate, filtered, and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (Biotage.RTM. 40M),
eluting with ethyl acetate/isohexane to give tert-butyl
4-(3-bromo-5-fluoropicolinamido)benzoate as a yellow solid. MS
(ESI) m/z 397.26 (M+H).
Step 2: tert-Butyl 4-(5-fluoro-3-phenylpicolinamido)benzoate
##STR00040##
[0229] A mixture of sodium carbonate (805 mg, 7.59 mmol),
tetrakis-(triphenylphosphine)palladium(0) (585 mg, 0.506 mmol),
phenyl boronic acid (617 mg, 5.06 mmol), and tert-butyl
4-(3-bromopicolinamido)benzoate (1 g, 2.53 mmol) in 3:1
dioxane-water (7 ml) was heated at 120.degree. C. for 1 hour in a
microwave reactor. The mixture was cooled, diluted with ethyl
acacate and then washed with aqueous sodium hydrogen carbonate. The
organic phase was dried over MgSO.sub.4, filtered and the solvent
was evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (Biotage.RTM. 25M), eluting
with ethyl acetate/isohexane to give tert-butyl
4-(5-fluoro-3-phenylpicolinamido)benzoate. MS (ESI) m/z 393.41
(M+H).
Step 3: tert-butyl
4-((6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpyridin-3-yl)oxy-
)piperidine-1-carboxylate
##STR00041##
[0231] NaH (173 mg, 4.32 mmol) was added to a stirred mixture of
tert-butyl 4-hydroxypiperidine-1-carboxylate (725 mg, 3.60 mmol) in
THF and the mixture was stirred at room temperature for 10 min. To
this mixture was then added tert-butyl
4-(5-fluoro-3-phenylpicolinamido)benzoate (942 mg, 2.4 mmol) in THF
at rt. The reaction was stirred at 80.degree. C. for overnight. The
mixture was cooled, aqueous sodium hydroxide was added and the
mixture was extracted with ethyl acacate. The combined organic
fractions were washed with brine, dried with MgSO.sub.4, filtered
and the solvent was evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel Biotage.RTM.
40M, eluting with EtOAc/isohexane to give tert-butyl
4-((6-((4-(tert-butoxy-carbonyl)phenyl)carbamoyl)-5-phenylpyridin-3-yl)ox-
y)piperidine-1-carboxylate. MS (ESI) m/z 574.63 (M+H).
Step 4: tert-butyl
4-((6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpiperidin-3-yl)o-
xy)piperidine-1-carboxylate and tert-butyl
4-((6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-cyclohexylpiperidin-3--
yl)oxy)piperidine-1-carboxylate
##STR00042##
[0233] Platinum(IV) oxide (20 mg, 0.088 mmol) was added to a
stirred room temperature mixture of
4-((6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpyridin-3-yl)oxy-
)piperidine-1-carboxylate (380 mg, 0.662 mmol) and methanol (10
ml). To this mixture was added 3 N aqueous HCl (1.987 mL). The
reaction was degassed and then stirred under a hydrogen balloon at
room temperature for 12 hours. The reaction mixture was filtered
through a celite pad, and aqueous sodium hydrogen carbonate was
added. The mixture was cooled, diluted with ethyl acetate and
washed with aqueous sodium hydrogen carbonate. The organic phase
was dried over MgSO.sub.4, filtered and the solvent was evaporated
under reduced pressure. The residue was purified by reverse phase
Gilson HPLC (CH.sub.3CN/Water) to yield tert-butyl
4-((6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpiperidin-3-yl)o-
xy)piperidine-1-carboxylate, MS (ESI) m/z 580.69 (M+H), and 14 mg
(3.6%) of tert-butyl
4-((6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-cyclohexylpiperidin-3--
yl)oxy)piperidine-1-carboxylate, MS (ESI) m/z 586.75 (M+H).
Step 5: tert-butyl
4-((6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1-((E)-3-(5-chloro-2-(1H-
-tetrazol-1-yl)phenyl)acryloyl)-5-phenylpiperidin-3-yl)oxy)piperidine-1-ca-
rboxylate
##STR00043##
[0235] N,N-Diisopropylethylamine (0.06 ml, 0.342 mmol) was added to
a stirred, room temperature mixture of HATU (87 mg, 0.228 mmol),
tert-butyl
4-((6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpiperidin-3-yl)o-
xy)piperidine-1-carboxylate (66 mg, 0.114 mmol), and
(E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid (57 mg,
0.228 mmol) in DMF (4 mL) and the mixture was stirred at room
temperature for 4 hours. The mixture was cooled and diluted with
ethyl acetate. The organic phase was washed with aqueous sodium
bicarbonate, dried over MgSO.sub.4, filtered and the solvent was
evaporated under reduced pressure to give a yellow solid. The
residue was purified by column chromatography on silica gel
(Biotage.RTM. 25M) eluting with ethyl acetate/isohexane to give 83
mg (90%) of tert-butyl
4-((6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1-((E)-3-(5-chloro-2-(1H-
-tetrazol-1-yl)phenyl)acryloyl)-5-phenylpiperidin-3-yl)oxy)piperidine-1-ca-
rboxylate (MS (ESI) m/z 812.80 (M+H).
Step 6:
4-(1-((E)-3-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-pheny-
l-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid
(Example 8)
##STR00044##
[0237] Trifluoroacetic acid (1 ml) was added to a stirred, room
temperature mixture of tert-butyl
4-((6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1-((E)-3-(5-chloro-2-(1H-
-tetrazol-1-yl)phenyl)acryloyl)-5-phenylpiperidin-3-yl)oxy)piperidine-1-ca-
rboxylate in DCM (2 ml) and the mixture was stirred at room
temperature for 1 hr. The reaction mixture was concentrated and
dissolved in MeOH and then purified by reverse phase Gilson HPLC
(CH.sub.3CN/Water) to give
4-(1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(pi-
peridin-4-yloxy)piperidine-2-carboxamido)benzoic acid as a white
solid. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.44 (s, 1H), 8.03
(s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.55 (dd, J=2.0, 8.5 Hz, 1H),
7.47 (d, J=8.5 Hz, 1H), 7.27-7.05 (m, 9H), 5.17 (d, J=6.0 Hz, 1H),
4.11 (d, J=7.5 Hz, 1H), 3.94 (br, 1H), 3.73-3.65 (m, 2H), 3.34-3.01
(m, 6H), 2.46 (m, 1H), 2.06-1.77 (m, 5H). (MS (ESI) m/z 656.63
(M+H).
Step 7:
4-((2S,3S,5S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylo-
yl)-3-phenyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic
acid (Example 9)
4-((2R,3R,5R)-1((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phe-
nyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid
(Example 10)
##STR00045##
[0239] From this product 10 mg was subjected to chiral separation
using Reverse phase HPLC (20.times.250 mm, Lux Cellulose-4, A: 0.1%
TFA in water, B: MeCN; Gradient: 75/25 to 45/55 AB in 12 minutes;
run time 13.5 minute, Flow rate: 15 ml/min) to afford
4-((2S,3S,5S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-p-
henyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid
(peak 2, Example 9) (MS (ESI) m/z 656.37 (M+H)) and
4-((2R,3R,5R)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-p-
henyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid
(peak 1, Example 10). MS (ESI) m/z 656.37 (M+H).
Example 11
[0240]
4-(1-((E)-3-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-cycloh-
exyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid
##STR00046##
[0241] This compound is synthesized in a similar way to
4-(1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(pi-
peridin-4-yloxy)piperidine-2-carboxamido)benzoic acid. (MS (ESI)
m/z 662.60 (M+H)).
Example 12
[0242]
4-(1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-phenyl-
-3-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid
##STR00047## ##STR00048##
Step 1: tert-Butyl 4-(3,5-dichloropicolinamido)benzoate
##STR00049##
[0244] N,N-Diisopropylethylamine (5.46 ml, 31.3 mmol) was added to
a stirred room temperature mixture of HATU (7.9 g, 20.8 mmol),
tert-butyl-4-aminobenzoate 2.4 g (12.5 mmol), and
3,5-dichloropicolinic acid (2 g, 10.4 mmol) in DMF 30 ml. The
mixture was stirred at room temperature overnight. The mixture was
cooled and diluted with ethyl acetate. The organic phase was washed
with aqueous sodium hydrogen carbonate, filtered, and the solvent
was evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (Biotage.RTM. 40M), eluting with
ethyl acetate/isohexane to give tert-butyl
4-(3,5-dichloropicolinamido)benzoate a yellow solid. MS (ESI) m/z
367.19 (M+H).
Step 2: tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-chloropyridin-3-yl)oxy-
)piperidine-1-carboxylate
##STR00050##
[0246] NaH (196 mg, 8.17 mmol) was added to a stirred mixture of
tert-butyl 4-hydroxypiperidine-1-carboxylate (1.206 g, 5.99 mmol)
in THF (40 ml) and the mixture was stirred at room temperature for
10 min. To this mixture was then added tert-butyl
4-(3,5-dichloropicolinamido)benzoate (2 g, 5.45 mmol) in THF at rt.
The reaction was stirred at 80.degree. C. for overnight. The
mixture was cooled, aqueous sodium hydroxide was added and the
mixture was extracted with ethyl acacate. The combined organic
fractions were washed with brine, dried with MgSO.sub.4, filtered
and the solvent was evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel Biotage.RTM.
40M, eluting with EtOAc/isohexane to give tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-chloropyridin-3-yl)oxy-
)piperidine-1-carboxylate. (MS (ESI) m/z 532.47 (M+H).
Step 3: tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpyridin-3-yl)oxy-
) piperidine-1-carboxylate
##STR00051##
[0248] A mixture of sodium carbonate (269 mg, 2.54 mmol),
tetrakis(triphenylphosphine)palladium(0) (585 mg, 0.506 mmol),
phenyl boronic acid (195 mg, 0.169 mmol), and tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-chloropyridin-3-yl)oxy-
)piperidine-1-carboxylate (450 mg, 0.846 mmol) in 3:1 dioxane-water
(7 ml) was heated at 120.degree. C. for 1 hour in a microwave
reactor. The mixture was cooled, diluted with ethyl acacate and
then washed with aqueous sodium hydrogen carbonate. The organic
phase was dried over MgSO.sub.4, filtered and the solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (Biotage.RTM. 25M), eluting
with ethyl acetate/isohexane to give tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpyridin-3-yl)oxy-
)piperidine-1-carboxylate. (MS (ESI) m/z 574.55 (M+H).
Step 4: tert-butyl
4-((2-(4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpiperidin-3-yl)ox-
y)piperidine-1-carboxylate
##STR00052##
[0250] Platinum(IV) oxide (40 mg, 0.176 mmol) was added to a
stirred room temperature mixture of tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpyridin-3-yl)oxy-
)piperidine-1-carboxylate (180 mg, 0.314 mmol) and methanol (10
ml). To this mixture was added 1 N aqueous HCl (3 mL). The reaction
was degassed and then stirred under a hydrogen balloon at room
temperature for 12 hours. The reaction mixture was filtered through
a celite pad, and aqueous sodium hydrogen carbonate was added. The
mixture was cooled, diluted with ethyl acetate and washed with
aqueous sodium hydrogen carbonate. The organic phase was dried over
MgSO.sub.4, filtered and the solvent was evaporated under reduced
pressure. The residue was purified by reverse phase Gilson HPLC
(CH3CN/Water) to yield tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpiperidin-3-yl)o-
xy) piperidine-1-carboxylate, MS (ESI) m/z 580.59 (M+H).
Step 5: tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1-((E)-3-(5-chloro-2-(1H-
-tetrazol-1-yl)phenyl)acryloyl)-5-phenylpiperidin-3-yl)oxy)piperidine-1-ca-
rboxylate
##STR00053##
[0252] N,N-Diisopropylethylamine (0.02 ml, 0.103 mmol) was added to
a stirred, room temperature mixture of HATU (30 mg, 0.078 mmol),
tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenylpiperidin-3-yl)o-
xy) piperidine-1-carboxylate (15 mg, 0.026 mmol), and
(E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid (20 mg,
0.78 mmol) in DMF (4 mL) and the mixture was stirred at room
temperature for 4 hours. The mixture was cooled and diluted with
ethyl acetate. The organic phase was washed with aqueous sodium
bicarbonate, dried over MgSO.sub.4, filtered and the solvent was
evaporated under reduced pressure to give a yellow solid. The
residue was purified by column chromatography on silica gel
(Biotage.RTM. 12M) eluting with ethyl acetate/isohexane to give
tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1-((E)-3-(5-chloro-2-(1H-
-tetrazol-1-yl)phenyl)acryloyl)-5-phenylpiperidin-3-yl)oxy)piperidine-1-ca-
rboxylate (MS (ESI) m/z 812.86 (M+H).
Step 6:
4-(1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-pheny-
l-3-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid
##STR00054##
[0254] Trifluoroacetic acid (0.5 ml) was added to a stirred, room
temperature mixture of tert-butyl
4-((2-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1-((E)-3-(5-chloro-2-(1H-
-tetrazol-1-yl)phenyl)acryloyl)-5-phenylpiperidin-3-yl)oxy)piperidine-1-ca-
rboxylate in DCM (1 ml) and the mixture was stirred at room
temperature for 1 hr. The reaction mixture was concentrated and
dissolved in MeOH and then purified by reverse phase Gilson HPLC
(CH.sub.3CN/Water) to give
4-(1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-phenyl-3-(pi-
peridin-4-yloxy)piperidine-2-carboxamido)benzoic acid as a white
solid. (MS (ESI) m/z 656.61 (M+H).
Example 13
Methyl
(4-{2-[4-amino-1'-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-
-2-enoyl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-4-yl}phe-
nyl)-carbamate
##STR00055## ##STR00056##
[0256] Step 1: Methyl 3-bromo-5-fluoropicolinate
[0257] 3-Bromo-5-fluoropicolinic acid (6.05 g, 27.5 mmol) and
potassium carbonate (11.4 g, 83.0 mmol) were mixed in DMF and
stirred at room temperature for 30 min. Iodomethane (2.57 mL, 41.3
mmol) was then added. The mixture was stirred at room temperature
for 1 h. The mixture was diluted with ethyl acetate, washed with
water (2.times.), brine, dried (MgSO.sub.4), filtered and the
solvent was evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel RediSep.RTM. 120 g,
eluting with EtOAc/isohexane (0-70%) to give the title compound as
a colorless oil. MS (ESI) m/z 236.05 (M+H).
Step 2: Methyl 5-fluoro-3-(4-fluorophenyl)picolinate
[0258] A 20 mL of microwave vial was charged with methyl
3-bromo-5-fluoropicolinate (2.00 g, 8.55 mmol),
(4-fluorophenyl)boronic acid (2.39 g, 17.09 mmol), sodium carbonate
(2.72 g, 25.6 mmol) and tetrakis (triphenylphosphine)palladium(0)
(0.50 g, 0.427 mmol). Then dioxane/water (8 mL/2 mL) was added. The
reaction mixture was treated under microwave at 130.degree. C. for
30 min. The mixture was concentrated under reduced pressure. The
residue was dissolved in EtOAc, washed with sat. sodium
bicarbonate, and brine, dried (MgSO.sub.4), filtered and
concentrated. The residue was dissolved in DCM, filtered off the
precipitate, which was the hydrolyzed acid of the starting
material. The filtrate was concentrated, then purified on ISCO
(0-50% EtOAc in hexane) to give the title compound as a white
solid. MS (ESI) m/z 250.52 (M+H).
Step 3: Methyl
5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-(4-fluorophenyl)picoli-
nate
[0259] To a solution of methyl
5-fluoro-3-(4-fluorophenyl)picolinate (2.02 g, 3.03 mmol) in DMF
(40 mL) was added methyl 5-fluoro-3-(4-fluorophenyl)picolinate
(0.637 g, 3.18 mmol) and potassium carbonate (0.461 g, 3.33 mmol).
The reaction mixture was heated at 115.degree. C. overnight. The
mixture was cooled, diluted with ethyl acetate, washed with water
(2.times.), brine, dried (MgSO.sub.4), filtered and the solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel, RediSep.RTM. 120 g, eluting
with EtOAc/isohexane (10-100%). The product was not pure. The
impure product was dissolved in 20 ml of 50% EtOAc/Hexane, kept in
the refrigerator overnight. Collected the crystals to obtained the
titled compound as an off white solid. MS (ESI) m/z 430.4
(M+H).
Step 4: Methyl
4-((tert-butoxycarbonyl)amino)-5'-(4-fluorophenyl)-[1,3'-bipiperidine]-6'-
-carboxylate bishydrochloride
[0260] Methyl
5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-(4-fluoro-phenyl)-pico-
linate (490 mg, 1.141 mmol), hydrogen chloride (2.282 ml, 2.282
mmol), followed by platinum(IV) oxide (51.8 mg, 0.228 mmol), were
mixed in 6 mL of MeOH. The reaction mixture was degassed and
stirred at room temperature using hydrogen balloon overnight. The
reaction mixture was filtered through a pad of celite, rinsed with
MeOH, and the filtrate was concentrated under reduced pressure. The
crude product was used without purification. MS (ESI) m/z 436.47
(M+H).
Step 5: 1'-benzyl 6'-methyl
4-((tert-butoxycarbonyl)amino)-5'-(4-fluorophenyl)-[1,3'-bipiperidine]-1'-
,6'-dicarboxylate
[0261] Methyl
4-((tert-butoxycarbonyl)amino)-5'-(4-fluorophenyl)-[1,3'-bipiperidine]-6'-
-carboxylate hydrochloride (537 mg, 1.138 mmol) was dissolved in 10
mL of DCM, TEA (0.793 ml, 5.69 mmol) was added. The solution was
cooled to 0.degree. C., to this solution was added benzyl
carbonochloridate (0.487 ml, 3.41 mmol) at 0.degree. C., then
stirred at 0.degree. C. for 3 hours. The reaction mixture was
diluted with DCM, washed with water, brine, dried (MgSO.sub.4),
filtered and concentrated. The residue was purified on ISCO (40 g
silica gel, 0-80% EtOAc in hexane) to give title compound as a
colorless gel. MS (ESI) m/z 570.56 (M+H).
Step 6:
1'-((benzyloxy)carbonyl)-4-((tert-butoxycarbonyl)amino)-5'-(4-fluo-
rophenyl)-[1,3'-bipiperidine]-6'-carboxylic acid
[0262] 1'-Benzyl 6'-methyl
4-((tert-butoxycarbonyl)amino)-5'-(4-fluorophenyl)-[1,3'-bipiperidine]-1'-
,6'-dicarboxylate (476 mg, 0.836 mmol) was dissolved in THF/MeOH (6
mL/4 mL), to this solution was added 2M aqueous LiOH (4.18 ml, 8.36
mmol), the mixture was stirred at room temperature for 2 h. The
organic solvents were removed under reduced pressure, leave some
water. More water was added to dissolve the compound. The fairly
clear solution was acidified with 1N HCl to pH.about.5, precipitate
formed. The mixture was extracted with ethyl acetate. The organic
fractions were washed with brine, dried (Mg.sub.2SO.sub.4),
filtered and the solvent was evaporated under reduced pressure to
give title compound as a white solid. MS (ESI) m/z 556.66
(M+H).
Step 7: 1'-benzyl
6'-(2-(4-((methoxycarbonyl)amino)phenyl)-2-oxoethyl)
4-((tert-butoxycarbonyl)amino)-5'-(4-fluorophenyl)-[1,3'-bipiperidine]-1'-
,6'-dicarboxylate
[0263] Cesium carbonate (63.3 mg, 0.194 mmol) was added to a
stirred mixture of
1'-((benzyloxy)carbonyl)-4-((tert-butoxycarbonyl)amino)-5'-(4-fluoropheny-
l)-[1,3'-bipiperidine]-6'-carboxylic acid (216 mg, 0.389 mmol) and
methyl (4-(2-chloroacetyl)phenyl)carbamate (88 mg, 0.389 mmol) in
DMF (3.6 mL) and the mixture was stirred at room temperature for 90
min. The mixture was diluted with ethyl acetate, washed with water
(2.times.), brine, dried (MgSO.sub.4), filtered and the solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel RediSep.RTM. 24 g, eluting with
EtOAc/isohexane (10-80%) to give title compound as a colorless
film. MS (ESI) m/z 747.69 (M+H).
Step 8: benzyl
4-((tert-butoxycarbonyl)amino)-5'-(4-fluorophenyl)-6'-(5-(4-((methoxycarb-
onyl)amino)phenyl)-1H-imidazol-2-yl)-[1,3'-bipiperidine]-1'-carboxylate
[0264] 1'-Benzyl
6'-(2-(4-((methoxycarbonyl)amino)phenyl)-2-oxoethyl)
4-((tert-butoxycarbonyl)amino)-5'-(4-fluorophenyl)[1,3'-bipiperidine]-1',-
6'-dicarboxylate was brought up in triflurotoluene (2 mL) in a 5 ml
microwave vial. Ammonium acetate (80 mg, 1.038 mmol) was added and
then the vial was capped. Microwave irradiation was used to heat
the reaction mixture at 150.degree. C. for 20 min. The reaction
mixture was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel RediSep.RTM. 24 g,
eluting with EtOAc/isohexane (10-100%) to give title compound as a
yellow solid. MS (ESI) m/z 727.56 (M+H).
Step 9: tert-Butyl
(1-(5-(4-fluorophenyl)-6-(4-(4-((methoxycarbonyl)amino)phenyl)-1l2-imidaz-
ol-2-yl)-1l2-piperidin-3-yl)piperidin-4-yl)carbamate
[0265] To a solution of benzyl
4-((tert-butoxycarbonyl)amino)-5'-(4-fluorophenyl)-6'-(5-(4-((methoxycarb-
onyl)amino)phenyl)-1H-imidazol-2-yl)-[1,3'-bipiperidine]-1'-carboxylate
(59 mg, 0.81 mmol) in EtOAc (2 mL) was added 5% Pd/C (34.6 mg,
0.016 mmol). The reaction mixture was treated under H.sub.2 balloon
for 6 h. The reaction mixture was filtered through a pad of celite,
rinsed with EtOAc, and the filtrate was concentrated under reduced
pressure. The crude product was used without purification. MS (ESI)
m/z 593.52 (M+H).
Step 10: tert-Butyl
(E)-(1'-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5'-(4-fluorophe-
nyl)-6'-(4-(4-((methoxycarbonyl)amino)phenyl)-1l2-imidazol-2-yl)-[1,3'-bip-
iperidin]-4-yl)carbamate
[0266] (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid
(23.34 mg, 0.093 mmol) and PyBOP (48.5 mg, 0.093 mmol) in THF (2
ml) was stirred at RT for 5 min. The mixture was then added to
tert-butyl
(1-(5-(4-fluorophenyl)-6-(4-(4-((methoxycarbonyl)amino)phenyl)-1l2-imidaz-
ol-2-yl)-1l2-piperidin-3-yl)piperidin-4-yl)carbamate (46 mg, 0.078
mmol) in THF (2 ml) followed by DIPEA (0.041 ml, 0.233 mmol). The
mixture was stirred at room temperature for 1 h. The mixture was
diluted with ethyl acetate, washed with water then brine, dried
over MgSO.sub.4, filtered and the solvent was evaporated under
reduced pressure. The residue was purified by column chromatography
on silica gel RediSep.RTM. 24 g, eluting with MeOH/DCM (0-3%). The
product was not pure. Second purification by preparative TLC was
used to give the title compound as an off white solid. MS (ESI) m/z
825.53 (M+H).
Step 11: tert-Butyl
(E)-(1'-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5'-(4-fluorophe-
nyl)-6'-(4-(4-((methoxycarbonyl)amino)phenyl)-1l2-imidazol-2-yl)-[1,3'-bip-
iperidin]-4-yl)carbamate
[0267] The mixture of stereoisomers from above, tert-butyl
(E)-(1'-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5'-(4-fluorophe-
nyl)-6'-(4-(4-((methoxycarbonyl)-amino)phenyl)-1l2
imidazol-2-yl)-[1,3'-bipiperidin]-4-yl)carbamate, was subjected to
chiral SFC using a ChiralPak.RTM. IA column (21.times.250 mm), 60%
2:1 IPA:MeCN/30% CO2, 55 ml/min, 100 bar, 35 C, 220 nm. Peak A 2.1
min, peak B 2.8 min. The title compound (peak 2) was isolated as a
white solid. MS (ESI) m/z 825.53 (M+H).
Step 12: Methyl
(4-{2-[4-amino-1'-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-eno-
yl}-5'-(4-fluorophenyl)-1,3'-bipiperidin-6'-yl]-1H-imidazol-4-yl}phenyl)ca-
rbamate (Example 13)
[0268] Peak 2 isolated as described above, tert-butyl
(E)-(1'-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5'-(4-fluorophe-
nyl)-6'-(4-(4-((methoxycarbonyl)-amino)phenyl)-1l2-imidazol-2-yl)-[1,3'-bi-
piperidin]-4-yl)carbamate was treated with 4M HCl/dioxane (0.3 mL)
at room temperature for 1 h. The mixture was concentrated under
reduced pressure to give title compound as a white solid. MS (ESI)
m/z 725.48 (M+H).
[0269] The following compounds may be prepared by someone skilled
in the art following a procedure similar to the one described
above.
TABLE-US-00002 LCMS Example Structure IUPAC Name [M + H]+ 14
##STR00057## 1'-{(2E)-3-[5-chloro-2- (1H-tetrazol-1-
yl)phenyl]prop-2-enoyl}- 5'-(4-fluorophenyl)-6'-(4-
pyridin-3-yl-1H-imidazol- 2-yl)-1,3'-bipiperidin-4- amine 653.63 15
##STR00058## (3'S,5'S,6'S)-1'-{(2E)-3-[5- chloro-2-(1H-tetrazol-1-
yl)phenyl]prop-2-enoyl}- 5'-(4-fluorophenyl)-6'-(4-
pyridin-3-yl-1H-imidazol- 2-yl)-1,3'-bipiperidin-4- amine 653.37 16
##STR00059## 4-{2-[4-amino-1'-{(2E)-3- [3-chloro-2-fluoro-6-
(trifluoromethyl)phenyl] prop-2-enoyl}-5'-(4- fluorophenyl)-1,3'-
bipiperidin-6'-yl]-1H- imidazol-5-yl}benzonitrile 695.3 17
##STR00060## 4-{2-[4-amino-1'-{(2E)-3- [3-chloro-2-fluoro-6-
(trifluoromethyl)phenyl] prop-2-enoyl}-5'-(4- fluorophenyl)-1,3'-
bipiperidin-6'-yl]-1H- imidazol-5-yl}benzonitrile 695.3 18
##STR00061## 4-{2-[4-amino-1'-{(2E)-3- [5-chloro-2-(1H-tetrazol-1-
yl)phenyl]prop-2-enoyl}- 5'-(4-fluorophenyl)-1,3'-
bipiperidin-6'-yl]-1H- imidazol-5-yl}benzonitrile 677.40 19
##STR00062## methyl (4-{2-[4-amino-1'- {(2E)-3-[3-chloro-2-
fluoro-6- (trifluoromethyl)phenyl] prop-2-enoyl}-5'-(4-
fluorophenyl)-1,3'- bipiperidin-6'-yl]-1H- imidazol-5-
yl}phenyl)carbamate 743.38 20 ##STR00063## methyl
(4-{2-[4-amino-1'- {(2E)-3-[3-chloro-2- fluoro-6-
(trifluoromethyl)phenyl] prop-2-enoyl}-5'-(4- fluorophenyl)-1,3'-
bipiperidin-6'-yl]-1H- imidazol-5- yl}phenyl)carbamate 743.44 21
##STR00064## methyl [4-(2-{4-amino-1'- [(2E)-3-(3-chloro-2,6-
difluorophenyl)prop-2- enoyl]-5'-(4-fluorophenyl)-
1,3'-bipiperidin-6'-yl}-1H- imidazol-4- yl)phenyl]carbamate 693.37
22 ##STR00065## methyl (4-{2- [(3'S,5'S,6'S)-4-amino-1'-
{(2E)-3-[5-chloro-2-(1H- tetrazol-1-yl)phenyl]prop-
2-enoyl}-5'-cyclopropyl- 1,3'-bipiperidin-6'-yl]-1H- imidazol-4-
yl}phenyl)carbamate 671.53
Example 23
4-((3R,5S,6
S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-phenyl-[3,4'-
-bipiperidine]-6-carboxamido)benzoic acid trifluoroacetic acid
salt
##STR00066##
[0270] Step 1: tert-Butyl
6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenyl-[3,4'-bipiperidine]-
-1'-carboxylate hydrochloride
[0271] To a solution of tert-butyl
6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenyl-5',6'-dihydro-[3,4'-
-bipyridine]-1'(2'H)-carboxylate (260 mg, 0.468 mmol) in MeOH (5
mL) was added 1N aqueous solution of hydrogen chloride (0.5 mL, 0.5
mmol), followed by dioxoplatinum hydrate (22.94 mg, 0.094 mmol) at
room temperature. The reaction mixture was degassed and stirred at
room temperature using hydrogen balloon for 7.5 h. The reaction
mixture was filtered through a pad of celite, rinsed with MeOH, and
the filtrate was concentrated under reduced pressure. The crude
product was used without purification. MS (ESI) m/z 564.4
(M+H).
Step 2: (E)-tert-butyl
6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1-(3-(5-chloro-2-(1H-tetrazo-
l-1-yl)phenyl)acryloyl)-5-phenyl-[3,4'-bipiperidine]-1'-carboxylate
[0272] DIEA (0.199 ml, 1.140 mmol) was added to a stirred mixture
of tert-butyl
6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenyl-[3,4'-bipiperidine]-
-1'-carboxylate hydrochloride (228 mg, 0.380 mmol),
(E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid (95 mg,
0.380 mmol) and HATU (173 mg, 0.456 mmol) in DMF (3 mL) and the
mixture was stirred at room temperature for 1 h. The mixture was
diluted with ethyl acetate, washed with water, brine, dried
(Mg.sub.2SO.sub.4), filtered and the solvent was evaporated under
reduced pressure. The residue was purified by column chromatography
on silica gel RediSep.RTM. 40 g, eluting with EtOAc/isohexane
(30-100%) to give the title compound as a pale yellow solid. MS
(ESI) m/z 796.0 (M+H).
Step 3: (E)-tert-butyl
6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1-(3-(5-chloro-2-(1H-tetrazo-
l-1-yl)phenyl)acryloyl)-5-phenyl-[3,4'-bipiperidine]-1'-carboxylate
[0273] The mixture of stereoisomers from above, (E)-tert-butyl
6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1-(3-(5-chloro-2-(1H-tetrazo-
l-1-yl)phenyl)-acryloyl)-5-phenyl-[3,4'-bipiperidine]-1'-carboxylate,
was subjected to chiral SFC using a OD-H (2.times.15 cm) column
eluting with 50% methanol/CO.sub.2, (100 bar, flow rate 60 ml/min).
Two enantiomers were isolated both as pale yellow solid. MS (ESI)
m/z 796.0 (M+H).
Step 4:
4-((3R,5S,6S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylo-
yl)-5-phenyl-[3,4'-bipiperidine]-6-carboxamido)benzoic acid
trifluoroacetic acid salt
Example 23
[0274] The above separated isomer (peak 2), (E)-tert-butyl
6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1-(3-(5-chloro-2-(1H-tetrazo-
l-1-yl)phenyl)acryloyl)-5-phenyl-[3,4'-bipiperidine]-1'-carboxylate
(65 mg, 0.082 mmol), was treated with TFA/DCM (0.5/1 mL) at RT for
50 min. Concentrated under reduced pressure. The residue was
purified by preparative HPLC Reverse phase (C-18), eluting with
Acetonitrile/Water+0.1% TFA, lyophilization to give title compound
as a colorless solid. MS (ESI) m/z 640.1 (M+H). 1H NMR .delta.
(ppm) (CH.sub.3OH-d4): 1.64 (2H, m), 1.69 (2H, m), 1.96-1.94 (1H,
m), 2.07 (2H, m), 2.41 (1H, d, J=12.57 Hz), 3.10-3.03 (2H, m),
3.25-3.19 (1H, m), 3.50 (2H, d, J=13.64 Hz), 3.72-3.77 (1H, m),
3.86 (1H, t, J=12.40 Hz), 4.13 (1H, d, J=12.88 Hz), 5.37 (1H, d,
J=6.04 Hz), 7.14 (1H, d, J=15.53 Hz), 7.33-7.20 (7H, m), 7.38 (1H,
d, J=7.41 Hz), 7.60 (1H, d, J=8.39 Hz), 7.69 (1H, dd, J=8.56, 2.29
Hz), 7.87 (2H, t, J=8.67 Hz), 8.18-8.15 (1H, m), 9.58 (1H, s).
TABLE-US-00003 LCMS Example Structure IUPAC Name [M + H]+ 24
##STR00067## 4-((3R,5R,6S)-1-((E)-3- (5-chloro-2-(1H-tetrazol-
1-yl)phenyl)acryloyl)-5- methyl-[3,4'- bipiperidine]-6-
carboxamido)benzoic acid 578.5 25 ##STR00068## 4-((3R,5R,6S)-1-(4-
(aminomethyl)-3- cyclopropylbenzoyl)-5- methy-1-[3,4'-
bipiperidine]-6- carboxamido)benzoic acid 519.5
Example 26
Methyl
(4-{2-[(3R,5S,6S)-1-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]pro-
p-2-enoyl}-5-cyclopropyl-3,4'-bipiperidin-6-yl]-1H-imidazol-4-yl}phenyl)ca-
rbamate
##STR00069##
[0275] Step 1. Methyl 5-chloro-3-cyclopropylpicolinate
[0276] A 500 mL round bottom flask was charged with methyl
3-bromo-5-chloropicolinate (6 g, 23.95 mmol), potassium
cyclopropyltrifluoroborate (5 g, 33.8 mmol), Reactant 3 (2.402 g,
3.59 mmol), cesium carbonate (23.41 g, 71.9 mmol), Toluene (108
ml), and Water (11.98 ml). The reaction mixture was stirred at
100.degree. C. for 18 hours, then cooled to room temperature. The
reaction mixture was partitioned between water and ethyl acetate.
The organic phase was dried over Na.sub.2SO.sub.4, filtered, and
concentrated to afford the crude product. The crude product was
loaded onto a 300 gram silica gel column. Flash chromatography
(0-10% hexanes-ethyl acetate) was used to isolate the product as a
colorless oil. MS (ESI) m/z 212.19 (M+H).
Step 2. 1'-tert-Butyl 6-methyl
5-cyclopropyl-5',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate
[0277] A 20 mL microwave vial was charged with methyl
5-chloro-3-cyclopropylpicolinate (0.5 g, 2.362 mmol), tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (913 mg, 2.95 mmol), 1,1'
bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (386 mg, 0.472 mmol), sodium carbonate (751
mg, 7.09 mmol), dioxane (8 ml), and water (2 ml). The reaction
mixture was heated in a microwave reactor at 150.degree. C. for 30
minutes. Four identical reactions were run as above and the
reaction mixtures were combined and filtered through a celite pad.
The filtrate was partitioned between water and ethyl acetate. The
organic phase was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude oil was loaded onto a 120 gram silica gel
column. Flash chromatography (0-100% EtOAc-hexanes) afforded the
desired product at high purity. MS (ESI) m/z 359.04 (M+H).
Step 3. 1'-tert-Butyl 6-methyl
5-cyclopropyl-[3,4'-bipiperidine]-1',6-dicarboxylate
hydrochloride
[0278] 1'-tert-Butyl 6-methyl
5-cyclopropyl-5',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate
(4.5 g, 12.55 mmol) was dissolved in 20 mL of methanol. To this
solution was added concentrated aqueous hydrogen chloride (1.031
ml, 12.55 mmol), degassed and added dioxoplatinum hydrate (0.308 g,
1.255 mmol) and rhodium(IV) oxide (0.373 g, 2.76 mmol). The mixture
was degassed and charged with hydrogen balloon and stirred at r.t.
for 6 hours. The reaction mixture was filtered through celite and
washed with ethyl acetate and concentrated. Used directly for the
next step. MS (ESI) m/z 367.25 (M+H).
Step 4. 1-Benzyl 1'-tert-butyl 6-methyl
5-cyclopropyl-[3,4'-bipiperidine]-1,1',6-tricarboxylate
[0279] 1'-tert-Butyl 6-methyl
5-cyclopropyl[3,4'-bipiperidine]-1',6-dicarboxylate hydrochloride
(4.95 g, 12.3 mmol) was dissolved in 20 mL of DCM. Triethylamine
(8.56 ml, 61.4 mmol) was added. The solution was cooled to
0.degree. C., to this solution was added benzyl carbonochloridate
(5.26 ml, 36.9 mmol) at 0.degree. C., then stirred at 0.degree. C.
for 3 hours. The reaction mixture was then washed with water,
brine, dried over sodium sulfate, filtered and concenrated,
purified on flash chromatography (120 g of silica, 0-80% EOAc in
hexane) to give final compound as colorless gel. MS (ESI) m/z
501.29 (M+H).
Step 5.
1-((Benzyloxy)carbonyl)-1'-(tert-butoxycarbonyl)-5-cyclopropyl-[3,-
4'-bipiperidine]-6-carboxylic acid
[0280] 1-Benzyl 1'-tert-butyl 6-methyl
5-cyclopropyl[3,4'-bipiperidine]-1,1',6-tricarboxylate (4.05 g,
8.09 mmol) was dissolved in 10 mL of THF and 4 mL of MeOH. To this
solution was added lithium hydroxide (0.969 g, 40.4 mmol) and
water. The mixture was stirred at 50.degree. C. for 4 hours until
completion. The organic solvent was removed, 1M HCl was added to
adjust PH to 4-5. Extracted with EtOAc, dried over sodium sulfate,
filtered and dried under vacuo. Used directly for the next step. MS
(ESI) m/z 487.27 (M+H).
Step 6. 1-Benzyl 1'-tert-butyl
6-(2-(4-((methoxycarbonyl)amino)phenyl)-2-oxoethyl)
5-cyclopropyl[3,4'-bipiperidine]-1,1',6-tricarboxylate
[0281] Cesium carbonate (1.231 g, 3.78 mmol) was added to a stirred
mixture of
1-((benzyloxy)carbonyl)-1'-(tert-butoxycarbonyl)-5-cyclopropyl-[3,4'-bipi-
peridine]-6-carboxylic acid (3.83 g, 4.72 mmol) and methyl
(4-(2-chloroacetyl)phenyl)carbamate (1.075 g, 4.72 mmol) were
dissolved in DMF (15 mL). The mixture was stirred at room
temperature for 2 h, then diluted with ethyl acacate, washed with
water (2.times.100 mL), brine, dried (MgSO.sub.4), filtered and the
solvent was evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel RediSep.RTM. 120 g,
eluting with EtOAc/isohexane (0-80%) to collect the product as a
colorless smear. MS (ESI) m/z 678.51 (M+H).
Step 7. 1-Benzyl 1'-tert-butyl
5-cyclopropyl-6-(5-(4-((methoxycarbonyl)amino)phenyl)-1H-imidazol-2-yl)-[-
3,4'-bipiperidine]-1,1'-dicarboxylate
[0282] 1-benzyl 1'-tert-butyl
6-(2-(4-((methoxycarbonyl)amino)phenyl)-2-oxoethyl)
5-cyclopropyl-[3,4'-bipiperidine]-1,1',6-tricarboxylate (508 mg,
0.750 mmol) was dissolved in 10 mL of toluene in 20 ml microwave
vial. Acetic acid ammonia salt (289 mg, 3.75 mmol) was added and
the reaction mixture was capped, prestirred for 30 sec. and then
heated under microwave irradiation at 148.degree. C. for 30 min.
The mixture was concentrated. Four identical reactions were run as
above and the reaction mixtures were mixed together, concentrated,
extracted with EtOAc and water, purified by column chromatography
on silica gel ReadySep 120 g, eluting with EtOAc/isohexane (10-80%)
to give final product. MS (ESI) m/z 658.53 (M+H).
Step 8. tert-Butyl
5-cyclopropyl-6-(5-(4-((methoxycarbonyl)amino)phenyl)-1H-imidazol-2-yl)-[-
3,4'-bipiperidine]-1'-carboxylate
[0283] 1-Benzyl 1'-tert-butyl
5-cyclopropyl-6-(5-(4-((methoxycarbonyl)amino)phenyl)-1H-imidazol-2-yl)-[-
3,4'-bipiperidine]-1,1'-dicarboxylate (1.05 g, 1.596 mmol) was
dissolved in 20 ml of EtOAc. To this solution purged with N.sub.2
was added palladium on carbon (0.170 g, 0.160 mmol). The mixture
was stirred under hydrogen for 30 hours. Filtered through celite
pad and washed with EtOAc, concentrated to give yellow solid. MS
(ESI) m/z 524.44 (M+H).
Step 9. (E)-tert-Butyl
1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-cyclopropyl-6-(4-(4-
-((methoxycarbonyl)amino)phenyl)-1H-imidazol-2-yl)-[3,4'-bipiperidine]-1'--
carboxylate
[0284] N-Ethyl-N-isopropylpropan-2-amine (0.699 ml, d 0.742 g/mL,
4.01 mmol) was added to a stirred mixture of HATU (508 mg, 1.337
mmol), tert-butyl
5-cyclopropyl-6-(4-(4-((methoxycarbonyl)amino)phenyl)-1H-imidazol-2-yl)-[-
3,4'-bipiperidine]-1'-carboxylate (700 mg, 1.337 mmol) and
(E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid (335 mg,
1.337 mmol) in DMF (10 mL). The mixture was stirred at room
temperature for 2 h. The mixture was diluted with ethyl acacate,
washed with water, brine, dried (Mg.sub.2SO.sub.4), filtered and
the solvent was evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel Redi Sep.RTM. 40 g,
eluting with EtOAc/isohexane (50-100%) to give product as yellow
solid. MS (ESI) m/z 756.59 (M+H).
Step 10. (3R,5S,6S)-tert-Butyl
1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-cyclopropyl-6-(-
4-(4-((methoxycarbonyl)amino)phenyl)-1H-imidazol-2-yl)-[3,4'-bipiperidine]-
-1'-carboxylate
[0285] (E)-tert-Butyl
1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-cyclopropyl-6-(4-(4-
-((methoxycarbonyl)amino)phenyl)-1H-imidazol-2-yl)-[3,4'-bipiperidine]-1'--
carboxylate (144 mg, 0.187 mmol) was submitted for chiral
separation, dissolved in isopropanol:DCM (3:1) at 10 mg/mL, inject
0.5 mL on OJ-H (2.times.25 cm) column, eluted with 35% isopropanol
(0.1% DEA) at 50 mL/min under CO.sub.2 100 bar pressure, detected
at UV 280 nm, yielded 45 mg of peak-1 (chemical purity>98%,
ee>98%) and 52 mg of peak-2 (chemical purity>99%, ee>99%).
The second peak was the desired compound. Retention time was at
11.13 min using the following analytical method: OJ-H
(25.times.0.46 cm), 25% isopropanol (DEA)/CO.sub.2, 100 bar, 3.0
mL/min, 220, 254 nm. MS (ESI) m/z 771.67 (M+H).
Step 11. Methyl
(4-{2-[(3R,5S,6S)-1-{(2E)-3[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-en-
oyl}-5-cyclopropyl-3,4'-bipiperidin-6-yl]-1H-imidazol-4-yl}phenyl)carbamat-
e (Example 26)
[0286] (3R,5S,6S)-tert-Butyl
1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-cyclopropyl-6-(-
4-(4-((methoxycarbonyl)amino)phenyl)-1H-imidazol-2-yl)-[3,4'-bipiperidine]-
-1'-carboxylate (45 mg, 0.059 mmol) was dissolved in 1 mL of DCM,
to this solution was added TFA (1 mL). the mixture was stirred at
room temperature for 1 hour. Solvent was removed under pressure.
The residue was purified on HPLC (10-90% acetonitrile in water with
0.05% TFA) to yield the title compound. MS (ESI) m/z 656.00
(M+H).
[0287] The following compound may be prepared by someone skilled in
the art following a procedure similar to the one described
above.
TABLE-US-00004 Exact Mass Example Structure IUPAC Name [M + H]+ 27
##STR00070## methyl (4-{2-[1-{(2E)- 3-[5-chloro-2-(1H- tetrazol-1-
yl)phenyl]prop-2- enoyl}-5-(4- fluorophenyl)-3,4'-
bipiperidin-6-yl]-1H- imidazol-4- yl}phenyl)carbamate 710.07
Example 28
Methyl
(4-{2-[(3R,5S,6S)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]pr-
op-2-enoyl}-5-cyclopropyl-1'-(methylsulfonyl)-3,4'-bipiperidin-6-yl]-1H-im-
idazol-4yl}phenyl)carbamate
##STR00071##
[0288] Step 1. (E)-methyl
(4-(2-(1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-cyclopropyl--
1'-(methylsulfonyl)-[3,4'-bipiperidin]-6-yl)-1H-imidazol-4-yl)phenyl)carba-
mate
[0289] Step 1: (E)-tert-butyl
1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-cyclopropyl-6-(4-(4-
-((methoxycarbonyl)amino)phenyl)-1H-imidazol-2-yl)-[3,4'-bipiperidine]-1'--
carboxylate (270 mg, 0.357 mmol) was dissolved in 4 mL of DCM and 2
mL of TFA. The mixture was stirred at room temperature for one
hour. The solvent was removed and the compound was dried under
vacuo.
[0290] Step 2: The material from step 1 in DCM (5 ml) at RT was
combined with triethylamine (0.299 mL, 2.142 mmol). The mixture
became a clear solution which was cooled to 0.degree. C.
Methanesulfonyl chloride (0.028 ml, 0.357 mmol) was added dropwise.
The mixture was stirred at 0.degree. C. for 1 h. The mixture was
quenched with aq. sat'd NaHCO.sub.3 then partitioned between water
and DCM. The organic phase washed with brine, dried (MgSO.sub.4),
filtered and the solvent was evaporated under reduced pressure. The
crude product was purified on ISCO (24 g, 0-10% MeOH in DCM) to
give the final product. MS (ESI) m/z 734.41 (M+H).
Step 2. Methyl
(4-{2-[(3R,5S,6S)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-e-
noyl}-5-cyclopropyl-1'-(methylsulfonyl)-3,4'-bipiperidin-6-yl]-1H-imidazol-
-4yl}phenyl)carbamate (Example 28)
[0291] The compound from above (145 mg, 0.187 mmol) was submitted
for chiral separation, dissolved in isopropanol:DCM (3:1) at 9
mg/mL, inject 0.5 mL on OJ-H (2.times.25 cm) column, eluted with
35% isopropanol (0.1% DEA) at 65 mL/min under CO.sub.2 100 bar
pressure, detected at UV 280 nm, yielded 57 mg of peak-1 (chemical
purity>99%, ee>98%) and 52 mg of peak-2 (chemical
purity>99%, ee>99%). The second peak was the desired compound
(Example 28). Retention time was at 7.09 min using the following
analytical method: OJ-H (25.times.0.46 cm), 40% isopropanol
(DEA)/CO.sub.2, 100 bar, 3.0 mL/min, 220, 254 nm. MS (ESI) m/z
734.41 (M+H).
Example 29
(2S,3S,5S)-1-{(2E)-3-[5-Chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-3--
(4-fluorophenyl)-N-1H-indazol-5-yl-5-morpholin-4-ylpiperidine-2-carboxamid-
e
##STR00072## ##STR00073##
[0292] Step 1:
3-Bromo-5-fluoro-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-
picolinamide
##STR00074##
[0294] To a mixture of 3-bromo-5-fluoropicolinic acid (334 mg, 1.52
mmol) and 1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-indazol-5-amine
(400 mg, 1.52 mmol) in DMF (5 mL) was added DIPEA (0.80 mL, 4.6
mmol) and HATU (1.155 g, 3.04 mmol) and the mixture was stirred at
room temperature for 30 h. The reaction mixture was quenched with
water (50 mL) and extracted with EtOAc (2.times.100 mL). The
combined organic layers were washed with brine (50 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography (0-30%
EtOAc in hexanes) to provide the title compound.
Step 2:
5-Fluoro-3-(4-fluorophenyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl-
)-1H-indazol-5-yl)picolinamide
##STR00075##
[0296] To a stirred solution of
3-bromo-5-fluoro-N-(1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indazol-5-yl-
)picolinamide (600 mg, 1.289 mmol) in 1,4-dioxane/H.sub.2O (4:1) (9
mL) were added 4-fluorophenylboronic acid (361 mg, 2.58 mmol),
Na.sub.2CO.sub.3 (410 mg, 3.87 mmol) and Pd(PPh.sub.3).sub.4 (298
mg, 0.258 mmol) at ambient temperature and the resulting mixture
was purged with nitrogen gas bubbling for 5 minutes. The mixture
was heated at 120.degree. C. for 1 hour using microwave
irradiation. The reaction mixture was cooled to room temperature
and partitioned between ethyl acetate, water and saturated aqueous
NaHCO.sub.3. The organic phase was separated. The combined organic
layers were washed with brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by combiflash flash chromatography (0-35%
EtOAc in hexanes) to provide the title compound.
Step 3:
3-(4-fluorophenyl)-5-morpholino-N-(1-((2-(trimethylsilyl)ethoxy)-m-
ethyl)-1H-indazol-5-yl)picolinamide
##STR00076##
[0298]
5-Fluoro-3-(4-fluorophenyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-
-1H-indazol-5-yl)picolinamide (250 mg, 0.520 mmol), morpholine
(0.048 mL, 0.55 mmol), and potassium carbonate (410 mg, 3.87 mmol)
were combined with 6 mL DMF. The reaction mixture was heated at
115.degree. C. overnight. By LCMS, all the starting material was
consumed. The reaction mixture was cooled to room temperature and
partitioned between ethyl acetate and water. The organic phase was
separated; the combined organic layers were washed with brine (100
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
combiflash flash chromatography (0-55% EtOAc in hexanes) to provide
the title compound and residual impurities. Additional purification
was accomplished by prep HPLC.
Step 4:
3-(4-Fluorophenyl)-N-(1H-indazol-5-yl)-5-morpholinopiperidine-2-ca-
rboxamide
##STR00077##
[0300] A 2 M aqueous solution of hydrogen chloride (40.0 equiv) was
added to
3-(4-fluorophenyl)-N-(1H-indazol-5-yl)-5-morpholinopiperidine-2-carbox-
amide (70.0 mg, 0.520 mmol), MeOH (5 mL), and platinum (IV) oxide
monohydrate (2.0 equiv). The resulting mixture was degassed with
hydrogen gas bubbling for 1 minute. The reaction was stirred under
a balloon pressure of hydrogen and reaction progress was monitored
by LCMS. After 30 h, the reaction was stopped and the crude product
was purified by reverse phase column chromotography to afford the
title compound. MS (ESI) m/z 424 (M+H).
Step 5:
(E)-1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-(4-fluor-
ophenyl)-N-(1H-indazol-5-yl)-5-morpholinopiperidine-2-carboxamide
##STR00078##
[0302] To a mixture of
(E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid (2.5 mg,
9.9 .mu.mol) and
3-(4-fluorophenyl)-N-(1H-indazol-5-yl)-5-morpholinopiperidine-2-carboxami-
de (4.0 mg, 9.5 .mu.mol) was added DIPEA (16 .mu.L, 94 .mu.mol) and
HATU (7.2 mg, 19 .mu.mol) and the mixture was stirred at room
temperature for 15 h. The reaction mixture was quenched with water
(5 mL) and extracted with EtOAc (2.times.25 mL). The combined
organic layers were washed with brine (50 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated and purified by Prep
HPLC using acetonitrile and water to afford the title compound. MS
(ESI) m/z 656.50 (M+H).
Step 6:
(2S,3S,5S)-1-{(2E)-3[5-Chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-en-
oyl}-3-(4-fluorophenyl)-N-1H-indazol-5-yl-5-morpholin-4-ylpiperidine-2-car-
boxamide (Example 29)
##STR00079##
[0304] The title compound was obtained using chiral SFC
(21.times.250 mm OD column eluting with 60% MeOH/CO.sub.2 and 0.2%
NH.sub.4OH at 100 bar and 35.degree. C.) starting from the racemic
sample of
(E)-1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-acryloyl)-3-(4-fluoropheny-
l)-N-(1H-indazol-5-yl)-5-morpholinopiperidine-2-carboxamide. MS
(ESI) m/z 656.51 (M+H).
[0305] The following compounds may be prepared by someone skilled
in the art following a procedure similar to the one described
above.
TABLE-US-00005 Example Structure IUPAC Name LCMS [M + H]+ 30
##STR00080## (2R,3R,5R)-1-{(2E)-3-[5- chloro-2-(1H-tetrazol-1-
y)phenyl]prop-2-enoyl}- 3-(4-fluorophenyl)-N-1H-
indazol-5-yl-5-piperazin- 1-ylpiperidine-2- carboxamide 655.65 31
##STR00081## (2S,3S,5S)-1-{(2E)-3-[5- chloro-2-(1H-tetrazol-1-
yl)phenyl]prop-2-enoyl}- 3-(4-fluorophenyl)-N-1H-
indazol-5-yl-5-piperazin- 1-ylpiperidine-2- carboxamide 655.51 32
##STR00082## (2S,3S,5S)-5-(4- acetylpiperazin-1-yl)-1-
{(2E)-3-[5-chloro-2-(1H- tetrazol-1-yl)phenyl]prop- 2-enoyl}-3-(4-
fluorophenyl)-N-1H- indazol-5-ylpiperidine-2- carboxamide
697.62
PREPARATION OF INTERMEDIATES
Preparation of (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic
acid
##STR00083##
[0306] Step 1: 5-Chloro-2-(1H-tetrazol-1-yl)benzoic acid
[0307] A suspension of 2-amino-5-chlorobenzoic acid (5.0 g, 29.1
mmol) and sodium azide (5.41 g, 83 mmol) in trimethyl orthoformate
(9.12 ml, 83 mmol) was cooled to 0.degree. C. Acetic acid (100 mL)
was added, and the mixture was stirred at 0.degree. C. for 3 hours.
The reaction was warmed to room temperature and then stirred at
room temperature overnight. The mixture was concentrated in vacuo,
and the residue was partitioned between ethyl acetate and 3 N HCl.
The organic phase was dried over MgSO.sub.4, filtered and the
solvent was evaporated under reduced pressure to give
5-chloro-2-(1H-tetrazol-1-yl)benzoic acid.
Step 2:
5-Chloro-N-methoxy-N-methyl-2-(1H-tetrazol-1-yl)benzamide
[0308] A mixture of 5-chloro-2-(1H-tetrazol-1-yl)benzoic acid (6.28
g, 28.0 mmol), PyBOP (14.55 g, 28.0 mmol),
N,O-dimethylhydroxylamine hydrochloride (2.73 g, 28.0 mmol),
N,N-diisopropylethylamine (14.65 mL, 84 mmol), and DCM (200 mL) was
stirred at room temperature over the weekend. After this time, the
reaction mixture was concentrated in vacuo. The residue was diluted
with ethyl acetate, washed with water, 10% aqueous KHSO.sub.4,
saturated aqueous NaHCO.sub.3, and brine. The organic phase was
dried over MgSO.sub.4, filtered and the solvent was evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel (Biotage.RTM. 65i), eluting with ethyl
acetate to give
5-chloro-N-methoxy-N-methyl-2-(1H-tetrazol-1-yl)benzamide as an off
white solid.
Step 3: 5-Chloro-2-(1H-tetrazol-1-yl)benzaldehyde
[0309] A solution of
5-chloro-N-methoxy-N-methyl-2-(1H-tetrazol-1-yl)benzamide (2.25 g,
8.41 mmol) in 30 mL of THF was added dropwise to a stirred,
-78.degree. C. 1 M solution of LiAlH.sub.4 (16.81 mL, 16.81 mmol)
in THF. Dropwise addition occurred over a period of 30 minutes, and
the mixture was stirred at -78.degree. C. for 1 hour. After this
time, 6.5 mL of cool water was added carefully. The resulting
mixture was diluted with ethyl acacate, and washed with 1 M
hydrochloric acid followed by brine. The organic phase was dried
over MgSO.sub.4, filtered and the solvent was evaporated under
reduced pressure to give 5-chloro-2-(1H-tetrazol-1-yl)benzaldehyde
as a light green solid.
Step 4: (E)-methyl
3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate
[0310] Methyl 2-(dimethoxyphosphoryl)acetate (1.402 ml, 9.72 mmol)
was added dropwise to a stirred, 0.degree. C. suspension of sodium
hydride (0.359 g, 8.97 mmol) in THF (60 mL). The reaction mixture
was allowed to warm up to room temperature and the stirred for 1
hour. A solution of 5-chloro-2-(1H-tetrazol-1-yl)benzaldehyde (1.56
g, 7.48 mmol) in THF (10 mL) was then added. The mixture was
stirred vigorously for 30 minutes. The mixture was poured into a
cold saturated NH.sub.4Cl solution. The resulting mixture was
extracted with ethyl acetate and the combined organic fractions
were washed with brine, dried over MgSO.sub.4, filtered and the
solvent was evaporated under reduced pressure. The residue was
recrystallized from ethyl acetate. The solid was collected and
dried in vacuo to give (E)-methyl
3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate as an off white
solid.
Step 5: (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid
[0311] A suspension of (E)-methyl
3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate (1.27 g, 4.80
mmol), 1 M aqueous sodium hydroxide (14.4 mL, 14.4 mmol) was
stirred at room temperature vigorously for 2.5 hours. The mixture
was neutralized with 1 N hydrochloric acid and then concentrated to
give a beige solid. The solid was partitioned between 1 N
hydrochloric acid and ethyl acetate. The organic layer was washed
with brine, dried and concentrated to give
(E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid as an off
white solid. MS (ESI) m/z 251.03 (M+H), 292.11 (M+CH.sub.3CN).
Preparation of methyl (4-(2-chloroacetyl)phenyl)carbamate
##STR00084##
[0312] Step 1: Methyl Phenylcarbamate
[0313] To a reaction mixture of aniline (500 g, 5.37 mol) in
dioxane (2 L) and H.sub.2O (2 L) was added NaOH (236 g, 5.91 mol).
After stirring for 1 hour, methyl chloroformate (550 g, 5.91 mol)
was added and the reaction mixture was stirred for 16 hours. The
reaction mixture was concentrated and diluted with EA and H.sub.2O.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated
to provide the title compounds as an oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 3.79 (s, 3H), 6.66 (m, 1H), 7.06-7.09
(m, 1H), 7.30-7.34 (m, 2H), 7.38-7.40 (m, 2H).
Step 2: Methyl (4-(2-chloroacetyl)phenyl)carbamate
[0314] A reaction mixture of methyl phenylcarbamate (500 g, 3.3
mol), 2-chloroacetyl chloride (556 g, 5 mol) and AlCl.sub.3 (1.3
kg, 10 mol) in 1,2-dichloroethane (5 L) was heated at 70.degree. C.
for 2 hours. The reaction mixture was allowed to cool down and
poured onto ice-H.sub.2O. The aqueous layer was extracted with DCM
three times. The combined organic layers were washed with H.sub.2O,
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified by column chromatography to provide the title compound as
an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 3.71 (s, 3H), 5.09 (s, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.94 (d,
J=8.8 Hz, 2H), 10.12 (s, 1H).
Preparation of tert-butyl
6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenyl-5',6'-dihydro-[3,4'-
-bipyridine]-1'(2'H)-carboxylate
##STR00085##
[0315] Step 1: tert-butyl
4-(3-bromo-5-chloropicolinamido)benzoate
[0316] A 500 mL round bottom flask was charged with
3-bromo-5-chloropicolinic acid (5 g, 21.2 mmol), tert-butyl
4-aminobenzoate (4.29 g, 22.2 mmol), HATU (8.04 g, 21.2 mmol), THF
(100 ml), and finally DIPEA (11.08 ml, 63.4 mmol). The resulting
mixture was stirred at room temperature over the weekend. After
this time, the reaction mixture was a yellowish suspension. LCMS
shows complete conversion to the desired product. The reaction
mixture was partitioned between ethyl acetate and saturated aqueous
NaHCO.sub.3. The organic phase was dried over Na.sub.2SO.sub.4 and
then filtered and concentrated to give the title compound as 12.08
grams of a yellow solid. MS (ESI) m/z 412.94 (M+H).
Step 2: tert-butyl 4-(5-chloro-3-phenylpicolinamido)benzoate
[0317] A 20 mL microwave vial was charged with tert-butyl
4-(3-bromo-5-chloropicolinamido)-benzoate (500 mg, 1.215 mmol),
phenylboronic acid (160 mg, 1.31 mmol), Pd(PPh.sub.3).sub.4 (105
mg, 0.091 mmol), sodium carbonate (322 mg, 3.04 mmol), dioxane (7.2
ml) and water (800 .mu.l). The reaction mixture was heated in the
microwave at 120.degree. C. for 45 minutes. A second reaction was
set up using twice the amounts described above. The crude product
was purified using silica gel flash chromatography to afford the
title compound. MS (ESI) m/z 409.07 (M+H).
Step 3: tert-butyl
6-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-5-phenyl-5',6'-dihydro-[3,4'-
-bipyridine]-1'(2'H)-carboxylate
[0318] A 20 mL microwave vial was charged with tert-butyl
4-(5-chloro-3-phenylpicolinamido)benzoate (0.2 g, 0.489 mmol),
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (0.19 g, 0.614 mmol),
1,1'-bis(diphenyl-phosphino)ferrocene-palladium(II) dichloride
dichloromethane complex (0.100 g, 0.122 mmol), sodium carbonate
(0.16 g, 1.510 mmol), dioxane (3.91 ml), and water (0.978 ml). The
reaction mixture was heated in a microwave reactor at 150.degree.
C. for 45 minutes. The reaction mixture was partitioned between
ethyl acetate and water. The organic phase was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to afford a purple oil
which was loaded onto a 80 gram silica gel column. Flash
chromatography (0%-40% EtOAc in hexanes) was used to isolated the
title compound. MS (ESI) m/z 556.33 (M+H).
Factor XIa Assay
[0319] The effectiveness of compounds of the present invention as
inhibitors of Coagulation Factor XIa can be determined using a
relevant purified serine protease, and an appropriate synthetic
substrate. The rate of hydrolysis of the chromogenic or fluorogenic
substrate by the relevant serine protease was measured both in the
absence and presence of compounds of the present invention. Assays
were conducted at room temperature or at 37.degree. C. Hydrolysis
of the substrate resulted in release of amino
trifluoromethylcoumarin (AFC), which was monitored
spectrofluorometrically by measuring the increase in emission at
510 nm with excitation at 405 nm. A decrease in the rate of
fluorescence change in the presence of inhibitor is indicative of
enzyme inhibition. Such methods are known to one skilled in the
art. The results of this assay are expressed as the inhibitory
constant, K.sub.i.
[0320] Factor XIa determinations were made in 50 mM HEPES buffer at
pH 7.4 containing 150 mM NaCl, 5 mM CaCl.sub.2, and 0.1% PEG 8000
(polyethylene glycol; JT Baker or Fisher Scientific).
Determinations were made using purified human Factor XIa at a final
concentration of 40 pM (Sekisui Diagnostics) and the synthetic
substrate, Z-Gly-Pro-Arg-AFC, TFA salt (Sigma #C0980) at a
concentration of 100 .mu.M.
[0321] Activity assays were performed by diluting a stock solution
of substrate at least tenfold to a final concentration .ltoreq.0.1
K.sub.m into a solution containing enzyme or enzyme equilibrated
with inhibitor. Times required to achieve equilibration between
enzyme and inhibitor were determined in control experiments.
Initial velocities of product formation in the absence (V.sub.o) or
presence of inhibitor (V.sub.i) were measured. Assuming competitive
inhibition, and that unity is negligible compared K.sub.m/[S],
[I]/e, and [I]/e (where [S], [I], and e respectively represent the
total concentrations, of substrate, inhibitor and enzyme), the
equilibrium constant (K.sub.i) for dissociation of the inhibitor
from the enzyme can be obtained from the dependence of
V.sub.o/V.sub.i on [I] shown in the following equation.
V.sub.o/V.sub.i=1+[I]/K.sub.i
[0322] The activities shown by this assay indicate that the
compounds of the invention may be therapeutically useful for
treating or preventing various cardiovascular and/or
cerebrovascular thromboembolic conditions in patients suffering
from unstable angina, acute coronary syndrome, refractory angina,
myocardial infarction, transient ischemic attacks, atrial
fibrillation, stroke such as thrombotic stroke or embolic stroke,
venous thrombosis, coronary and cerebral arterial thrombosis,
cerebral and pulmonary embolism, atherosclerosis, deep vein
thrombosis, disseminated intravascular coagulation, and reocclusion
or restenosis of recanalized vessels.
Factor XIa Inhibition (IC.sub.50) (nM))
TABLE-US-00006 [0323] 1 0.8 2 11.4 3 27.2 4 2.2 5 104.8 6 141.8 7
0.4 8 4.7 9 2.5 10 306.5 11 6.1 12 154.8 13 1.7 14 139 15 82.1 16
35.6 17 889 18 16.5 19 67.8 20 128.3 21 407.1 22 671.2 23 640.1 24
578.5 25 519.4 26 656.2 27 710.2 28 651.9 29 81.1 30 767.5 31 40.9
32 72.2
[0324] The present invention is not limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope
of this invention. Indeed, various modifications of the invention
in addition to those shown and described herein will become
apparent to those skilled in the relevant art and are intended to
fall within the scope of the appended claim.
[0325] Compounds of the Formula (I) can be administered both as a
monotherapy and in combination with other therapeutic agents,
including antithrombotics (anticoagulants and platelet aggregation
inhibitors), thrombolytics (plasminogen activators), other
profibrinolytically active substances, hypotensives, blood sugar
regulators, lipid-lowering agents and antiarrhythmics.
[0326] The Factor XIa inhibitors can also be co-administered with
suitable anticoagulants, including, but not limited to, other
Factor XIa inhibitors, thrombin inhibitors, thrombin receptor
antagonists, Factor VIIa inhibitors, Factor Xa inhibitors, Factor
IXa inhibitors, Factor XIIa inhibitors, adenosine diphosphate
antiplatelet agents (e.g., P2Y12 antagonists), fibrinogen receptor
antagonists (e.g., to treat or prevent unstable angina or to
prevent reocclusion after angioplasty and restenosis), other
anticoagulants such as aspirin, and thrombolytic agents such as
plasminogen activators or streptokinase to achieve synergistic
effects in the treatment of various vascular pathologies. Such
anticoagulants include, for example, apixaban, dabigatran,
cangrelor, ticagrelor, vorapaxar, clopidogrel, edoxaban,
mipomersen, prasugrel, rivaroxaban, and semuloparin. For example,
patients suffering from coronary artery disease, and patients
subjected to angioplasty procedures, would benefit from
coadministration of fibrinogen receptor antagonists and thrombin
inhibitors. Factor XIa inhibitors may be administered first
following thrombus formation, and tissue plasminogen activator or
other plasminogen activator is administered thereafter.
[0327] Alternatively or additionally, one or more additional
pharmacologically active agents may be administered in combination
with a compound of the invention. The additional active agent (or
agents) is intended to mean a pharmaceutically active agent (or
agents) that is active in the body, including pro-drugs that
convert to pharmaceutically active form after administration, which
is different from the compound of the invention, and also includes
free-acid, free-base and pharmaceutically acceptable salts of said
additional active agents when such forms are sold commercially or
are otherwise chemically possible. Generally, any suitable
additional active agent or agents, including but not limited to
anti-hypertensive agents, additional diuretics,
anti-atherosclerotic agents such as a lipid modifying compound,
anti-diabetic agents and/or anti-obesity agents may be used in any
combination with the compound of the invention in a single dosage
formulation (a fixed dose drug combination), or may be administered
to the patient in one or more separate dosage formulations which
allows for concurrent or sequential administration of the active
agents (co-administration of the separate active agents). Examples
of additional active agents which may be employed include but are
not limited to angiotensin converting enzyme inhibitors (e.g.,
alacepril, benazepril, captopril, ceronapril, cilazapril, delapril,
enalapril, enalaprilat, fosinopril, imidapril, lisinopril,
moveltipril, perindopril, quinapril, ramipril, spirapril,
temocapril, or trandolapril); angiotensin II receptor antagonists
also known as angiotensin receptor blockers or ARBs, which may be
in free-base, free-acid, salt or pro-drug form, such as azilsartan,
e.g., azilsartan medoxomil potassium (EDARBI.RTM.), candesartan,
e.g., candesartan cilexetil (ATACAND.RTM.), eprosartan, e.g.,
eprosartan mesylate (TEVETAN.RTM.), irbesartan (AVAPRO.RTM.),
losartan, e.g., losartan potassium (COZAAR.RTM.), olmesartan, e.g.,
olmesartan medoximil (BENICAR.RTM.), telmisartan (MICARDIS.RTM.),
valsartan (DIOVAN.RTM.), and any of these drugs used in combination
with a thiazide-like diuretic such as hydrochlorothiazide (e.g.,
HYZAAR.RTM., DIOVAN HCT.RTM., ATACAND HCT.RTM.), etc.); potassium
sparing diuretics such as amiloride HCl, spironolactone,
epleranone, triamterene, each with or without HCTZ; neutral
endopeptidase inhibitors (e.g., thiorphan and phosphoramidon);
aldosterone antagonists; aldosterone synthase inhibitors; renin
inhibitors; enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES
8891; SQ 34017; aliskiren
(2(S),4(S),5(S),7(S)--N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,-
7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamid
hemifumarate) SPP600, SPP630 and SPP635); endothelin receptor
antagonists; vasodilators (e.g. nitroprusside); calcium channel
blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem,
felodipine, gallopamil, niludipine, nimodipine, nicardipine);
potassium channel activators (e.g., nicorandil, pinacidil,
cromakalim, minoxidil, aprilkalim, loprazolam); sympatholitics;
beta-adrenergic blocking drugs (e.g., acebutolol, atenolol,
betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartate,
nadolol, propranolol, sotalol, timolol); alpha adrenergic blocking
drugs (e.g., doxazocin, prazocin or alpha methyldopa); central
alpha adrenergic agonists; peripheral vasodilators (e.g.
hydralazine); lipid lowering agents, e.g., HMG-CoA reductase
inhibitors such as simvastatin and lovastatin which are marketed as
ZOCOR.RTM. and MEVACOR.RTM. in lactone pro-drug form and function
as inhibitors after administration, and pharmaceutically acceptable
salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such
as atorvastatin (particularly the calcium salt sold in
LIPITOR.RTM.), rosuvastatin (particularly the calcium salt sold in
CRESTOR.RTM.), pravastatin (particularly the sodium salt sold in
PRAVACHOL.RTM.), and fluvastatin (particularly the sodium salt sold
in LESCOL.RTM.); a cholesterol absorption inhibitor such as
ezetimibe (ZETIA.RTM.), and ezetimibe in combination with any other
lipid lowering agents such as the HMG-CoA reductase inhibitors
noted above and particularly with simvastatin (VYTORIN.RTM.) or
with atorvastatin calcium; niacin in immediate-release or
controlled release forms, niacin receptor agonists such as acipimox
and acifran, as well as niacin receptor partial agonists; metabolic
altering agents including insulin sensitizing agents and related
compounds for the treatment of diabetes such as biguanides (e.g.,
metformin), meglitinides (e.g., repaglinide, nateglinide),
sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide,
glyburide, tolazamide, tolbutamide), thiazolidinediones also
referred to as glitazones (e.g., pioglitazone, rosiglitazone),
alpha glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl
peptidase inhibitors, (e.g., sitagliptin (JANUVIA.RTM.),
alogliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin,
gemigliptin), ergot alkaloids (e.g., bromocriptine), combination
medications such as JANUMET.RTM. (sitagliptin with metformin), and
injectable diabetes medications such as exenatide and pramlintide
acetate; or with other drugs beneficial for the prevention or the
treatment of the above-mentioned diseases including but not limited
to diazoxide; and including the free-acid, free-base, and
pharmaceutically acceptable salt forms, pro-drug forms, e.g.,
esters, and salts of pro-drugs of the above medicinal agents, where
chemically possible. Trademark names of pharmaceutical drugs noted
above are provided for exemplification of the marketed form of the
active agent(s); such pharmaceutical drugs could be used in a
separate dosage form for concurrent or sequential administration
with a compound of the invention, or the active agent(s) therein
could be used in a fixed dose drug combination including a compound
of the invention.
[0328] Typical doses of Factor XIa inhibitors of the invention in
combination with other suitable anti-platelet agents,
anticoagulation agents, or thrombolytic agents may be the same as
those doses of Factor XIa inhibitors administered without
coadministration of additional anti-platelet agents,
anticoagulation agents, or thrombolytic agents, or may be
substantially less that those doses of thrombin inhibitors
administered without coadministration of additional anti-platelet
agents, anticoagulation agents, or thrombolytic agents, depending
on a patient's therapeutic needs.
[0329] The compounds are administered to a mammal in a
therapeutically effective amount. By "therapeutically effective
amount" it is meant an amount of a compound of the present
invention that, when administered alone or in combination with an
additional therapeutic agent to a mammal, is effective to treat
(i.e. prevent, inhibit or ameliorate) the thromboembolic and/or
inflammatory disease condition or treat the progression of the
disease in a host.
[0330] The compounds of the invention are preferably administered
alone to a mammal in a therapeutically effective amount. However,
the compounds of the invention can also be administered in
combination with an additional therapeutic agent, as defined below,
to a mammal in a therapeutically effective amount. When
administered in a combination, the combination of compounds in
preferably, but not necessarily, a synergistic combination.
Synergy, as described for example by Chou and Talalay, Adv. Enzyme
Regul. 1984, 22, 27-55, occurs when the effect (in this case,
inhibition of the desired target) of the compounds when
administered in combination is greater than the additive effect of
the compounds when administered alone as a single agent. In
general, a synergistic effect is most clearly demonstrated at
suboptimal concentrations of the compounds. Synergy can be in terms
of lower cytotoxicity, increased anticoagulant effect, or some
other beneficial effect of the combination compared with the
individual components.
[0331] By "administered in combination" or "combination therapy" it
is meant that the compound of the present invention and one or more
additional therapeutic agents are administered concurrently to the
mammal being treated. When administered in combination each
component may be administered at the same time or sequentially in
any order at different points in time. Thus, each component may be
administered separately but sufficiently closely in time so as to
provide the desired therapeutic effect.
* * * * *